Immediate release abuse-deterrent granulated dosage forms

ABSTRACT

Described are immediate release oral dosage forms that contain abuse-deterrent features. In particular, the disclosed dosage forms provide deterrence of abuse by ingestion of multiple individual doses. In addition, the disclosed dosage forms provide protection from overdose in the event of accidental or intentional ingestion of multiple individual doses.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/US2015/064403, filed on Dec.8, 2015, which claims the benefit of U.S. Provisional Application No.62/088,901, filed Dec. 8, 2014, the entire contents of both of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the field of oral dosage forms thatcontain abuse-deterrent features, in particular including immediaterelease dosage forms that contain a drug that is commonly susceptible toabuse.

BACKGROUND

Pharmaceutical products, including both prescription andover-the-counter pharmaceutical products, while useful for improvinghealth of a person in need, are also susceptible to intentional andunintentional abuse and overdosing. Examples of commonly abused activepharmaceutical ingredients include psychoactive drugs, anxiolytics,sedative hypnotics, stimulants, depressants, and analgesics such asnarcotic analgesics, among others. A complete list of specific drugcompounds that are commonly abused would be lengthy; a short listing ofsome classes of drugs commonly abused includes opioids and morphinederivatives, barbiturates, amphetamines, ketamine, and other drugs thatcan cause psychological or physical dependence.

Some common techniques for intentionally abusing a drug begin with anabuser obtaining a solid dosage form such as an orally administeredtablet or capsule, and crushing the solid dosage form into a powder. Thepowder may be administered by an abuser by nasal insufflation (i.e.,“snorting”) to introduce the drug to the abuser's bloodstreamintranasally. Alternately, the crushed dosage form may be combined witha solvent that is capable of dissolving the drug (active pharmaceuticalingredient, or “API”), and the solvent with the dissolved drug may beinjected directly into an abuser's bloodstream.

Alternatively, with immediate release oral dosage forms, an abuser mightsimply ingest multiple units (e.g., tablets) of the dosage formtogether, e.g., simultaneously. Each one of the multiple dosage formunits—immediately releases an amount of drug to produce a short-termconcentration spike of the drug in the user's bloodstream and a desired“high” in the user.

The pharmaceutical industry has identified various mechanisms ofadapting drug compositions and oral dosage forms that can be useful todiscourage abuse of oral dosage forms. Pharmaceutical companies havestudied dosage forms that contain a nasal irritant or an effervescentagent, which can cause irritation or pain in a nasal passage if thedosage form is crushed and then snorted, thus discouraging abuse bynasal insufflation. Pharmaceutical companies studied adding gellingpolymers to dosage forms to prevent abuse by injection. If the dosageform is crushed to a powder and combined with a small amount of solvent,the gelling polymer can cause the combination to take the form of ahighly viscous liquid or gel that cannot be administered by injection.Another possible abuse deterrent may be addition of an emetic agentwhich can deter abuse by causing emesis on ingestion of multiple doses.Another abuse deterrent involves adding an antagonist of an API to adosage form that will substantially block the effect of the drug.

Although the pharmaceutical industry has identified of a variety ofabuse deterrent (sometimes referred to as “abuse-resistant”) featuresuseful with oral dosage forms, there is continuing need to improve andidentify new abuse deterrent features to inhibit or prevent abuse oroverdosing of active pharmaceutical ingredients.

SUMMARY

The following description relates to oral dosage forms that are usefulfor immediate release of an active pharmaceutical ingredient or “API.”

The dosage form can be designed to release the API as desired in animmediate release dosage form, and can also include one or a combinationof feature that will prevent or deter abuse of the API. The abusedeterrent features described herein can be included singly or in anycombination in an immediate release dosage form.

As a first type of abuse deterrent feature, a dosage form as describedcan include a gelling polymer to prevent or compromise abuse practiceswherein the dosage form is crushed and then combined with a small amountof a solvent to produce a liquid composition that contains aconcentrated amount of API and that can be delivered to an abuser usinga syringe. The gelling polymer can be any polymer useful to achieve thisfunctionality, and can be placed in the dosage form at any location toallow the gelling polymer to perform as described and still allowimmediate release of the API. A gelling polymer can be included in acore of a coated of core-shell particle or in a matrix of a dosage formthat suspends the core-shell particles. The core may contain any amountof gelling polymer, such as from 0 to 100 percent gelling polymer basedon a total weight of the core. Alternately, the core in a core-shellparticle may comprise a filler, e.g., up to 100 percent filler, such asa sugar sphere or microcrystalline cellulose sphere (up to 100 percentmicrocrystalline cellulose spheres such as those available under thetrade name Celphere®).

Another type of abuse deterrent feature can be a wax that alone or withother ingredients, e.g., the gelling polymer, is effective incompromising abuse practices wherein a dosage form is crushed andcombined with a solvent to produce a liquid composition that can beabused by nasal insufflation or delivered to an abuser using a syringe.The wax can additionally inhibit or prevent an abuser from grinding thedosage form into a powder because upon grinding the wax will smear asopposed to fracturing or powdering. Similar to the gelling polymer, waxcan be included in a dosage form at any location that allows the wax tofunction as an abuse deterrent feature while not interfering with animmediate release profile of the API. For example, a wax can be includedin a core of a coated particle. A core may contain any amount of wax,such as from 0 to 100 percent wax based on a total weight of the core,such as up to 50, 75, or 80 weight percent wax based on a total weightof the core.

Still another type of abuse deterrent feature can be a filler or binderthat alone or in combination with other ingredients can compromise abusepractices wherein a dosage form is being crushed and combined with asmall amount of a solvent to produce a liquid composition that can bedelivered to an abuser using a syringe. The filler or binder can inhibitor prevent an abuser from grinding the dosage form into a powder becauseupon grinding, the polymeric filler or binder will smear as opposed tofracturing or powdering. The filler or binder can be included in adosage form in any manner and location that allows the filler or binderto function as an abuse deterrent feature while not interfering with animmediate release profile of the API. For example, a filler or bindercan be included in a core of a coated particle. A core may contain anyamount of polymeric filler or binder such as from 0 to 100 percentfiller or binder on a total weight of the core, or up to 50, 75, or 80weight percent filler or binder based on a total weight of the core.

Yet another type of abuse deterrent feature can be a film layer thatsurrounds or covers API in a dosage form and that is optionallyresistant to being dissolved by one or more of the solvents commonlyused by abusers to dissolve an API for injection, including water andC₁-C₄ alcohols such as ethanol, methanol, and mixtures thereof. The filmlayer may be prepared from any film material that is disposed as acontinuous layer on a coated particle at a location to enclose andsurround the API. Examples of film layers can optionally and preferablyprovide properties of a solvent-resistant film, which is a film that isslow or difficult to dissolve in a limited or small volume of one thesolvents commonly used by abusers to dissolve API of a dosage form. Toaccess an API of a dosage form an abuser may grind the dosage form andcombine the ground dosage form with a solvent (as described) in anattempt to produce a solution that contains the concentrated API and thesolvent, and that may be efficiently injected or snorted. By being slowto dissolve or insoluble in one or more of water, or a C₁-C₄ alcoholsuch as ethanol, methanol, etc., a solvent-resistant film layer thatsurrounds API of a dosage form can prevent an abuser from easilyaccessing and so manipulating the API.

In exemplary embodiments, an immediate release dosage form can includethese features in a coated particle, such as a core-shell particle. Anexemplary core-shell particle can include a core and one or more layerssurrounding the core. For such a core-shell particle, the API may beincluded in the core, or in one or more layers surrounding the core, orin both the core and one or more layers surrounding the core. The dosageform may additionally contain core-shell particles that do not includethe API in either the core, or in any layer surrounding the core. Thecore can include any one or more of: a gelling polymer, wax, binder, orfiller, alone or in combination. Alternately, the core may comprise amicrocrystalline cellulose or sugar sphere.

A film layer may surround and enclose the core, or an API-containinglayer that is disposed around the core. The film layer may preferably bea solvent-resistant film in the form of a continuous coating that coversthe core, which contains API, or that covers an API-containing layer orcoating disposed around the core, or that covers a core that has noAPI-containing layer or coating disposed around the core and contains noAPI.

According to other various embodiments, a coated particle as describedherein can be useful in a dosage form that includes one or more optionalabuse deterrent features, and a matrix such as a compressed matrix thatis formed to allow for immediate release of the API present in thecoated particles. An exemplary matrix composition may compriseadditional gelling polymer, disintegrant, or both additional gellingpolymer and disintegrant. The expression “additional gelling polymer” asused above means an amount of gelling polymer that is in addition to anamount of gelling polymer present in the coated particles. Theadditional gelling polymer may be the same or different in nature,chemistry, molecular weight, etc., as compared to the gelling polymerthat is included in the coated particles. A disintegrant as a componentof the matrix may be useful to facilitate release of the API of thedosage form, e.g., API present in the coated particles.

The active pharmaceutical ingredient included in the dosage form,especially in the coated particle surrounded by a film layer (e.g., asolvent resistant film), can be any active pharmaceutical ingredientdesired to be administered orally, and may in particular be a type ofactive pharmaceutical ingredient that is commonly susceptible to abuse.Examples of active pharmaceutical ingredients that are considered to becommonly susceptible to abuse include psychoactive drugs, tranquilizers,sedative hypnotics, anxiolytics, stimulants, depressants, and narcoticanalgesics, among others. Certain more specific classes of drugscommonly abused includes opioids, barbiturates, benzodiazepines,amphetamines, as well as many other drugs that are known to causepsychological or physical dependence.

Dosage forms of the present description can be useful as immediaterelease dosage forms, and may also include abuse deterrent features asdescribed. The abuse deterrent features can discourage or prevent abuseby nasal insufflation, by injection, and can also be effective toprevent or significantly limit the success of abuse by the commonmethods (especially with immediate release oral dosage forms) of orallytaking multiple dosage form units together. The final mode of abuse(sometimes referred to herein as “multi-tablet dosing”) is oftenparticularly difficult to deter, especially in immediate release oraldosage forms, making these described dosage forms particularly useful asabuse-deterrent oral immediate release dosage forms.

Embodiments of the described dosage forms can be effective in theabsence of other types of abuse deterrent features such as nasalirritants, emetic agents, buttering agents, and effervescent agents, toinhibit nasal insufflation or other forms of abuse, or the inclusion ofdrug antagonists of the subject drug.

In one aspect, the invention relates to an immediate release dosage formthat includes core-shell particles. The core-shell particles include: aninner core containing a gelling polymer; at least one layer surroundingthe core, the at least one layer including a film layer surrounding thecore; and an active pharmaceutical ingredient. The active pharmaceuticalingredient is also surrounded by the film layer that surrounds the core.

In another aspect, the invention relates to an immediate release dosageform that includes core-shell particles. The core-shell particlesinclude a core and an active pharmaceutical layer surrounding the core.The active pharmaceutical layer contains an active pharmaceuticalingredient. The core contains less than 5 weight percent of a totalamount of the active pharmaceutical ingredient in the core-shellparticles.

In yet another aspect the invention relates to an immediate releasedosage form that contains core-shell particles. The core-shell particlesinclude: a core and an active pharmaceutical ingredient. The dosage formfurther includes a matrix. The matrix includes disintegrant and anadditional amount of gelling polymer.

-   -   In still another aspect, the invention relates to an immediate        release dosage form that includes two types of core-shell        particles. One type of core-shell particles includes a core and        an active pharmaceutical layer surrounding the core as discussed        above. The core of these particles optionally contains less than        5 weight percent of the total amount of the API in that        core-shell particle, and in some instances contains less than 1        weight percent of the total amount of the API in that core-shell        particle, or even contains no significant amount of the API. The        other type of core shell particles comprise the core, but do not        contain an active pharmaceutical layer surrounding the core.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B, and 1C illustrate embodiments of core-shell particles asdescribed, in cross section.

FIGS. 2A and 2B illustrate embodiments of core-shell particles asdescribed, in cross section.

FIG. 3 is a perspective view of an embodiment of a dosage form asdescribed.

FIG. 4 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of hydrocodone bitartrate in 0.1NHCl media as a function of time.

FIG. 5 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of acetaminophen in 0.1N HCl mediaas a function of time.

FIG. 6 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of hydrocodone bitartrate in 0.1NHCl media as a function of time.

FIG. 7 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of acetaminophen in 0.1N HCl mediaas a function of time.

FIG. 8 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of hydrocodone bitartrate in 0.1NHCl media as a function of time.

FIG. 9 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of acetaminophen in 0.1N HCl mediaas a function of time.

FIG. 10 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of oxycodone hydrochloride fromoxycodone hydrochloride/acetaminophen tablets (5/325 mg/tablet and7.5/325 mg/tablet of oxycodone hydrochloride/acetaminophen) in 0.1N HClmedia as a function of time.

FIG. 11 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of acetaminophen from oxycodonehydrochloride/acetaminophen tablets (5/325 mg/tablet and 7.5/325mg/tablet of oxycodone hydrochloride/acetaminophen) in 0.1N HCl media asa function of time.

FIG. 12 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of hydrocodone bitartrate fromhydrocodone bitartrate/acetaminophen tablets (5/325 mg/tablet and7.5/325 mg/tablet of hydrocodone bitartrate/acetaminophen) in 0.1N HClmedia as a function of time.

FIG. 13 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of acetaminophen from hydrocodonebitartrate/acetaminophen tablets (5/325 mg/tablet and 7.5/325 mg/tabletof hydrocodone bitartrate/acetaminophen) in 0.1N HCl media as a functionof time.

FIG. 14 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of hydrocodone bitartrate fromhydrocodone bitartrate/acetaminophen tablets (10/325 mg/tablet ofhydrocodone bitartrate/acetaminophen, tested both as intact tablets andcrushed tablets) in 0.1N HCl media as a function of time.

FIG. 15 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of acetaminophen from hydrocodonebitartrate/acetaminophen tablets (10/325 mg/tablet of hydrocodonebitartrate/acetaminophen, tested both as intact tablets and crushedtablets) in 0.1N HCl media as a function of time.

FIG. 16 shows a plot of plasma levels of hydrocodone as a function oftime following simultaneous administration to healthy naltrexone-blockedhuman male subjects of six hydrocodone bitartrate/acetaminophen tablets(10 mg/tablet hydrocodone bitartrate and 325 mg acetaminophen).

FIG. 17 shows a plot of plasma levels of hydrocodone as a function oftime following simultaneous administration to healthy naltrexone-blockedhuman male subjects of eight hydrocodone bitartrate/acetaminophentablets (10 mg/tablet hydrocodone bitartrate and 325 mg acetaminophen).

FIG. 18 shows a plot of plasma levels of acetaminophen as a function oftime following simultaneous administration to healthy naltrexone-blockedhuman male subjects of six hydrocodone bitartrate/acetaminophen tablets(10 mg/tablet hydrocodone bitartrate and 325 mg acetaminophen).

FIG. 19 shows a plot of plasma levels of acetaminophen as a function oftime following simultaneous administration to healthy naltrexone-blockedhuman male subjects of eight hydrocodone bitartrate/acetaminophentablets (10 mg/tablet hydrocodone bitartrate and 325 mg acetaminophen).

FIGS. 20a and 20b show two plots comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation to a marketed/conventionalhydrocodone/acetaminophen (FIG. 20a showing plasma levels ofhydrocodone, and FIG. 20b showing plasma levels of acetaminophen), as afunction of time following simultaneous administration to healthynaltrexone-blocked human male subjects of ten hydrocodonebitartrate/acetaminophen tablets (10 mg/tablet hydrocodone bitartrateand 325 mg acetaminophen).

FIGS. 21a and 21b show two plots comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation to a marketed/conventionalhydrocodone/acetaminophen (FIG. 21a showing plasma levels ofhydrocodone, and FIG. 21b showing plasma levels of acetaminophen), as afunction of time following simultaneous administration to healthynaltrexone-blocked human male subjects of two hydrocodonebitartrate/acetaminophen tablets (10 mg/tablet hydrocodone bitartrateand 325 mg acetaminophen).

FIGS. 22a and 22b show two plots comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation (Treatment 1) to amarketed/conventional hydrocodone/acetaminophen (Treatment 2), (FIG. 22ashowing plasma levels of hydrocodone, and FIG. 22b showing plasma levelsof acetaminophen), as a function of time following simultaneousadministration to healthy naltrexone-blocked human male subjects of sixhydrocodone bitartrate/acetaminophen tablets (10 mg/tablet hydrocodonebitartrate and 325 mg acetaminophen).

FIGS. 23a and 23b show two plots comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation (Treatment 1) to amarketed/conventional hydrocodone/acetaminophen (Treatment 2), (FIG. 23ashowing plasma levels of hydrocodone, and FIG. 23b showing plasma levelsof acetaminophen), as a function of time following simultaneousadministration to healthy naltrexone-blocked human male subjects of tenhydrocodone bitartrate/acetaminophen tablets (10 mg/tablet hydrocodonebitartrate and 325 mg acetaminophen).

FIGS. 24a, 24b, and 24c show plots comparing the area under curve (AUC)of hydrocodone for of the test hydrocodone/acetaminophen formulation(Treatment 1) to a marketed/conventional hydrocodone/acetaminophen(Treatment 2) indicating hydrocodone exposure after 1 hour post-dose forsimultaneous administration of 2 tablets (FIG. 24a ), 6 tablets (FIG.24b ) and 10 tablets (FIG. 24c ).

FIGS. 25a, 25b, and 25c show plots comparing the area under curve (AUC)of hydrocodone for of the test hydrocodone/acetaminophen formulation(Treatment 1) to a marketed/conventional hydrocodone/acetaminophen(Treatment 2) indicating hydrocodone exposure after 2 hours post-dosefor simultaneous administration of 2 tablets (FIG. 25a ), 6 tablets(FIG. 25b ) and 10 tablets (FIG. 25c ).

FIG. 26 shows a plot comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation (Treatment 2) to amarketed/conventional hydrocodone/acetaminophen (Treatment 1), showingmean (±SD) plasma concentration-time profiles of hydrocodone over 6hours following administration to healthy naltrexone-blocked human malesubjects of 2 tablets of hydrocodone bitartrate/acetaminophen (10mg/tablet hydrocodone bitartrate and 325 mg/tablet acetaminophen).

FIG. 27 shows a plot comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation (Treatment 2) to amarketed/conventional hydrocodone/acetaminophen (Treatment 1), showingmean (±SD) plasma concentration-time profiles of hydrocodone over 6hours following administration to healthy naltrexone-blocked human malesubjects of 6 tablets of hydrocodone bitartrate/acetaminophen (10mg/tablet hydrocodone bitartrate and 325 mg/tablet acetaminophen).

FIG. 28 shows a plot comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation (Treatment 2) to amarketed/conventional hydrocodone/acetaminophen (Treatment 1), showingmean (±SD) plasma concentration-time profiles of hydrocodone over 6hours following administration to healthy naltrexone-blocked human malesubjects of 10 tablets of hydrocodone bitartrate/acetaminophen (10mg/tablet hydrocodone bitartrate and 325 mg/tablet acetaminophen).

FIG. 29 shows a plot comparing the area under the plasma concentrationcurve (AUC) of hydrocodone over the first hour (AUC₀₋₁) for of the testhydrocodone/acetaminophen formulation (Treatment 2) to amarketed/conventional hydrocodone/acetaminophen (Treatment 1) indicatinghydrocodone exposure after 2 hours post-dose for simultaneousadministration of 2 tablets, 4 tablets, 6 tablets, 8 tablets and 10tablets (10 mg/tablet hydrocodone bitartrate and 325 mg/tabletacetaminophen).

FIG. 30 shows a plot comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation (Treatment 2) to amarketed/conventional hydrocodone/acetaminophen (Treatment 1), showingmean (±SD) plasma concentration-time profiles of acetaminophen over 6hours following administration to healthy naltrexone-blocked human malesubjects of 2 tablets of hydrocodone bitartrate/acetaminophen (10mg/tablet hydrocodone bitartrate and 325 mg/tablet acetaminophen).

FIG. 31 shows a plot comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation (Treatment 2) to amarketed/conventional hydrocodone/acetaminophen (Treatment 1), showingmean (±SD) plasma concentration-time profiles of acetaminophen over 6hours following administration to healthy naltrexone-blocked human malesubjects of 6 tablets of hydrocodone bitartrate/acetaminophen (10mg/tablet hydrocodone bitartrate and 325 mg/tablet acetaminophen).

FIG. 32 shows a plot comparing pharmacokinetics of the testhydrocodone/acetaminophen formulation (Treatment 2) to amarketed/conventional hydrocodone/acetaminophen (Treatment 1), showingmean (±SD) plasma concentration-time profiles of acetaminophen over 6hours following administration to healthy naltrexone-blocked human malesubjects of 10 tablets of hydrocodone bitartrate/acetaminophen (10mg/tablet hydrocodone bitartrate and 325 mg/tablet acetaminophen).

FIG. 33 shows a plot comparing the area under the plasma concentrationcurve (AUC) of acetaminophen over the first hour (AUC₀₋₁) for of thetest hydrocodone/acetaminophen formulation (Treatment 2) to amarketed/conventional hydrocodone/acetaminophen (Treatment 1) indicatinghydrocodone exposure after 2 hours post-dose for simultaneousadministration of 2 tablets, 4 tablets, 6 tablets, 8 tablets and 10tablets (10 mg/tablet hydrocodone bitartrate and 325 mg/tabletacetaminophen).

FIGS. 34A and 34B show plots of single tablet dissolution of oxycodoneHCl/acetaminophen tablets prepared according to Examples 100 and 103 (10mg/tablet oxycodone HCl and 325 mg/tablet acetaminophen) in pH 4.5sodium acetate buffer as a function of time (FIG. 34A showing release ofoxycodone HCl, and FIG. 34B showing release of acetaminophen).

FIGS. 35A and 35B show plots of multiple tablet dissolution of oxycodoneHCl/acetaminophen tablets prepared according to Examples 100 (data forrelease for 2-, 6- and 12-tablets) and 103 (data for 6- and 12-tablets)(10 mg/tablet oxycodone HCl and 325 mg/tablet acetaminophen) in 0.1N HClas a function of time (FIG. 35A showing release profile for oxycodoneHCl, and FIG. 35B showing the release profile for acetaminophen).

FIGS. 36A and 36B show plots of single tablet dissolution of hydrocodonebitartrate/acetaminophen tablets prepared according to Examples 107 and110 (10 mg/tablet hydrocodone bitartrate and 325 mg/tabletacetaminophen) in pH 4.5 sodium acetate buffer as a function of time(FIG. 36A showing release of hydrocodone bitartrate, and FIG. 36Bshowing release of acetaminophen).

FIGS. 37A and 37B show plots of multiple tablet dissolution (12 tablets)of hydrocodone bitartrate/acetaminophen tablets prepared according toExamples 107 and 110 (10 mg/tablet hydrocodone bitartrate and 325mg/tablet acetaminophen) in 0.1 N HCl as a function of time (FIG. 37Ashowing release profiles for hydrocodone bitartrate, and FIG. 37Bshowing the release profiles for acetaminophen).

FIG. 38 shows plots of single tablet dissolution of Esketamine HCltablets prepared according to Examples 114A, 114B and 114C (100mg/tablet Esketamine HCl) in pH 4.5 sodium acetate buffer as a functionof time.

FIG. 39 shows plots of multiple tablet dissolution (12 tablets) ofEsketamine HCl tablets prepared according to Examples 114A, 114B and114C (100 mg/tablet Esketamine HCl) in 0.1 N HCl as a function of time.

DETAILED DESCRIPTION

The present description relates to immediate release dosage forms thatinclude one or more abuse deterrent features for reducing the potentialfor a) parenteral abuse, b) abuse by nasal insufflation (“snorting”),and c) abuse by simultaneous oral ingestion of multiple oral dosage formunits (tablets or capsules) of a drug. These abuse deterrent featuresare achieved by preparing the dosage form to include certain structuralfeatures and certain ingredients that have now been determined toeffectively prevent an abuser from realizing the intended biologicaleffect of the drug abuse by using certain presently-common methods usedto abuse the API. Advantageously, a dosage form prepared to contain oneor more of the described abuse deterrent features, as a deterrent toabuse of one or more API that is commonly susceptible to abuse, canstill be constructed to provide immediate release of the one or more APIupon normal therapeutic use by oral ingestion.

As used herein, expressions such as “abuse deterrent” and “preventing”or “deterring” or “inhibiting” practices and processes associated withthe abuse and overdose of drugs, relate to features of the claimedformulations that provide significant physical and chemical impedimentsto these practices and processes. The objective in such deterrenceincludes both making abuse practices significantly more difficult tocarry out, and making any product resulting from an attempt to carry outsuch abuse practices on the claimed formulations significantly lessdesirable, less profitable, and less abusable to the potential abuser.

The term “immediate release” refers to a dosage form that upon oralingestion by a human releases substantially all of a contained activepharmaceutical ingredient into a gastrointestinal tract for biologicaluptake in a short time. In vitro methods of measuring a release profileof a dosage form, for the purpose of determining whether a dosage formexhibits an immediate release or extended release dissolution profile,are known in the pharmaceutical arts. By such methods, examples ofimmediate release dosage forms as described herein can be measured to becapable of releasing substantially all of a total amount of at least onetype of active pharmaceutical ingredient (e.g., an API commonlysusceptible to abuse) contained in the dosage form (e.g., at least 75,80, or 90 weight percent of the total amount of the API in a dosageform) into a solution (e.g., acidic aqueous solution) of a suitable pHwithin 240 minutes, e.g., in less than 180 minutes, less than 90minutes, or less than 60, 30, 15, or 5 minutes. For example, a releaseprofile of a dosage form of the present description may be measured by amethod that exposes the dosage form to a volume of up to 900 milliliters(e.g., 300 milliliters, or 900 milliliters, based on various testmethods) of hydrochloric acid (0.01 to 0.1N) (e.g., aqueous hydrochloricacid) at a pH of from 1 to 2, and at a temperature of 37 degreesCelsius. According to some embodiments, the dosage forms describedherein, demonstrate not less than 90% of API released in 60 minutes whenadministered at therapeutic doses, wherein the release profiles may beevaluated, for example, by dissolution in 300 mL of 0.1N HCl media usingUSP II apparatus at 50 RPM paddle speed and 37° C. A release profile ofa dosage form of the present description may alternatively be measuredby a method that exposes the dosage form to a volume of up to 900milliliters (e.g., 300 milliliters, 400 milliliters, or 900 milliliters,based on various test methods) of an aqueous buffer solution (e.g., anacetate buffer solution) at a pH that isrepresentative of the pHconditions of a fed stomach, e.g., at a pH of about 4.5, and at atemperature of 37 degrees Celsius.

The term “extended release” can be defined as not more than 95% releaseof the API at 60 minutes, wherein the release profiles may be evaluated,for example, by dissolution in 300 mL of 0.1N HCl media using USP IIapparatus at 50 RPM paddle speed and 37° C. According to someembodiments, the dosage forms described herein, demonstrate:

-   -   not less than 90% of API released in 60 minutes when        administered at therapeutic doses; and    -   not more than 95% release of the API at 60 minutes when        administered at supratherapeutic doses;        wherein the release profiles may be evaluated by dissolution in        300 mL of 0.1N HCl media using USP II apparatus at 50 RPM paddle        speed and 37° C. In this context, a “supratherapeutic dose” will        be understood to correspond to administration of five or more,        six or more, seven or more, eight or more, nine or more, ten or        more, eleven or more, or twelve or more individual dose units,        e.g., tablets, simultaneously. It will also be understood that        administering multiple individual dose units simultaneously        would reasonably include administering those multiple doses        sequentially over a short time interval, e.g., over an interval        of less than 60 minutes, less than 30 minutes, less than 15        minutes, less than 5 minutes or less than one minute.

Dosage forms as described can be formulated to provide an immediaterelease profile of an API, and can also be prepared to include effectiveor advantageous abuse deterrent features that are effective to deterabuse of the same API (e.g., one that is commonly susceptible to abuse)that exhibits the immediate release profile. The combination ofimmediate release of an API with broad abuse resistance of the same APIfor multiple abuse modalities including multi-tablet dosing, asdescribed herein, is not believed to be previously known. Moreparticularly, dosage forms as described herein can provide an immediaterelease profile of an API, and can at the same time include abusedeterrent features that provide general abuse deterrence or abuseresistance of the same API. The dosage forms can also be morespecifically characterized as resistant to certain common methods ofabuse, such as 1) abuse by injection (e.g., by steps that includegrinding a dosage form and dissolving API of the dosage form), 2) abuseby nasal insufflation (e.g., also by grinding and optionally dissolvingAPI of a dosage form), and 3) abuse by multi-tablet dosing by oralconsumption, meaning simultaneous oral ingestion of multiple orexcessive quantities of orally administered dosage forms such as tabletsor capsules. The third mode of abuse, multi-tablet dosing, isparticularly common with immediate release dosage forms and isparticularly difficult to defend against by design of a dosage formstructure or by formulation. Accordingly, that the presently-describeddosage forms can be effective to prevent or deter abuse (or evenaccidental overdose) by the mode of multi-tablet dosing can be aparticularly useful feature of the dosage forms described herein.

In vitro testing of exemplary dosage forms as described herein indicatesthat exemplary dosage forms provide deterrence against abuse bymulti-tablet dosing. More specifically, in vitro testing of exemplarydosage forms was performed by conducting dissolution testing of one ormore dosage forms (tablets) in 300 milliliters (or 400 millilitersaccording to some testing methods) of 0.1N HCL maintained at 37 degreesCelsius using a 50 RPM paddle speed. See, Example 26 (a) and FIGS. 4 and5 herein. As shown at FIGS. 4, 5, 6, 7, 8 and 9, the amount (percentageper tablet) of API (opioid) or APAP (acetaminophen) released in themedia is reduced with an increase in the number of tablets. The dataalso suggest that the tested dosage forms are effective to preventincreased levels of API uptake in an individual who would accidentallyingest multiple tablets, preventing or reducing the risk of anunintentional overdose of the API. (In FIGS. 4 and 5, the 1 tablet and 2tablet dosage forms are as prepared in Example 3, infra, and the 5tablet, 8 tablet, and 12 tablet dosage forms are as prepared in Example5, infra. The tablets used in FIGS. 6, 7, 8 and 9 are as prepared as perExample 17.)

In addition, in vitro testing as described herein indicates thatexemplary dosage forms provide deterrence against abuse by multi-tabletdosing, even if the dosage form is crushed prior toadministration/testing. Specifically, in vitro testing was performed byconducting dissolution testing of multiple (twelve) crushed tabletsaccording to the same protocol as described above for testing intacttablets (i.e., in 300 or 900 milliliters of 0.1N HCl maintained at 37degrees Celsius using a 50 RPM paddle speed). See, Example 93 and FIGS.14-15 herein. As shown in FIGS. 14-15, the percentage of the API (theopioid and APAP) that was released in the media was reduced with anincrease in the number of crushed tablets. This data suggests that thedosage forms are effective to prevent increased levels of API uptake inan individual who would ingest multiple crushed tablets, and therebyprevent or reduce the risk of an overdose of the API. The tablets usedin Example 94, which provided the data shown in FIGS. 14-15 wereprepared as per Example 93.)

In vivo testing in naloxone-blocked healthy human male subjects has beenundertaken. This testing was designed to determine if previous in vitrodissolution data utilizing multiple tablets translates to humans. Doseescalation from 2 tablets through 10 tablets was carried out with nosafety signals identified.

Preliminary results demonstrated that simultaneous administration of 2tablets was similar to administration of 2 tablets of a commerciallyavailable hydrocodone/acetaminophen combination product (NORCO). Thetest formulation differentiated from the commercially availablehydrocodone/acetaminophen combination product over the first 4 hours forhydrocodone at a dose of ≧6 tablets. Findings were similar foracetaminophen.

Preliminary PK data from an early study for the two through ten tabletcohorts provided the data included herein in FIGS. 16 to 27(a-c). In theFigures, “Treatment 1” refers to administration ofhydrocodone/acetaminophen (10 mg/325 mg) formulated according to theinvention described herein. “Treatment 2” refers to administration ofhydrocodone/acetaminophen (10 mg/325 mg) in a conventional commerciallyavailable immediate release formulation.

FIGS. 16 to 25(a-c) were prepared prior to completion of the study.FIGS. 16 to 19 provide only preliminary data and FIGS. 20 to 25(a-c)provide final data from the first phase of this testing. The PK resultsmay suggest that when opioid formulations as described herein areadministered as recommended (<2 tablets), those formulations will haveproperties consistent with an immediate release opioid, but when takenat supra-therapeutic doses (>6 tablets), the formulations will behavemore like an extended release opioid formulation.

The final results from the completed study were consistent with thepreliminary findings. Following administration ofhydrocodone/acetaminophen (10 mg/325 mg) (formulated according to theinvention) or a conventional commercially available immediate releaseformulation (NORCO), overall exposure to hydrocodone and acetaminophen(as assessed by AUC0-∞) was generally comparable. However, earlysystemic exposure to hydrocodone and acetaminophen was lower and peakconcentrations occurred later following administration of theformulation according to the invention—as compared with the conventionalformulation. The relative difference between the 2 products'pharmacokinetic profiles became substantially larger as the number oftablets administered was increased. The differences were most notableover the first 1 to 2 hours after dosing and were sustained throughapproximately 3 to 6 hours after dosing for the increased tabletadministrations.

Accordingly, dosage forms as described herein provide a method ofpreventing or attenuating a short-term concentration spike of the drugin the bloodstream of a patient who is prescribed the drug, or in thebloodstream of an abuser who consumes the drug for recreationalpurposes, in the event that a patient or the abuser intentionally orunintentionally consumes a supratherapeutic dose of the drug. Thus,dosage forms as described herein can provide a method whereby a drugoverdose may be prevented reduced or attenuated, when a patientintentionally or unintentionally consumes a supratherapeutic dose of thedrug. Also, in some instances, dosage forms as described herein mayprovide a greater amount of time for medical intervention in the case ofintentional or accidental overdose.

By “supratherapeutic is meant a dose that exceeds what would normally beprescribed for therapy, for example a dose in excess of two, three,four, five, six, seven, eight, nine, ten, eleven or twelve individualdose units (e.g., tablets, capsules, etc.).

As one type of abuse deterrent feature, a dosage form as described caninclude one or more gelling polymers. A gelling polymer can act as anabuse deterrent feature by compromising abuse practices wherein anactive pharmaceutical ingredient of a dosage form is being dissolved ina small volume of solvent or being accessible or easily isolatable ifcombined with solvent with the gelling polymer also present. A gellingpolymer can also deter or prevent abuse of an API in a dosage form byincreasing the viscosity of a combination of the ground dosage form withsolvent (especially a “small volume” of solvent) to a viscosity that issufficiently high to prevent the combination or the API from being takenup by and injected using a syringe. A preferred gelling polymercontained in a ground dosage form, when exposed to a limited volume (or“small volume”) of solvent such as a C₁₋₄ alcohol (e.g., ethanol ormethanol) or water, can form a non-injectable mass ranging from aninsoluble mass, to a gel, to a viscous slurry, each of which exhibits aviscosity that substantially prevents either uptake by or injection froma needle of a hypodermic syringe.

Suitable gelling polymers include one or a combination of polymers that,as part of a dosage form, upon contact of the dosage form with a smallvolume of solvent, will absorb the solvent and swell to form a viscousor semi-viscous substance that significantly reduces or minimizes theamount of free solvent that can contain an amount of a solubilized APIand that can be drawn into a syringe. The gelled polymer can also reducethe overall amount of drug extractable with the solvent by entrappingthe drug in a gel matrix.

The gelling polymer can be present in the dosage form at a location andin an amount that together allow the gelling polymer to produce aviscous gel in the event of an abuser grinding the dosage form andcombining the crushed dosage form with a solvent. On the other hand, thegelling polymer, as present in the dosage form, will preferably notinterfere with desired dissolution of the dosage form, the desiredrelease (immediate release) of API from the dosage form, or the uptakeof the API by a patient ingesting the intact immediate release dosageform for an intended therapeutic purpose. An exemplary location for thegelling polymer is in a coated particle that also includes activepharmaceutical ingredient, such as in a core or in a layer coated tosurround the core; wherein an amount of active pharmaceutical ingredientis contained in either the core, or a layer coated to surround the core,or is contained in both. Another exemplary location is within a matrixused to form a compressed tablet, a capsule (e.g., a compressedcapsule), a caplet, or another type of dosage form that contains acoated particle that contains active pharmaceutical ingredient. Gellingpolymer may also be present, in the core, or in a layer surrounding thecore, of a coated particle that does not include an activepharmaceutical ingredient.

The gelling polymer can be present in a dosage form at any desiredamount and at any portion of, or location in a dosage form structure.The amount of gelling polymer can be any useful amount, meaning anamount that can produce an abuse-deterrent viscous mixture or gel if thedosage form is crushed, ground, powdered, etc., and mixed with solvent.A useful amount of total gelling polymer in a dosage form may be in arange from 0.5 to 90 weight percent gelling polymer based on a totalweight of the dosage form, e.g., from 0.7 to 20, or 2 to 15 weightpercent gelling polymer based on total weight of the dosage form.

These amounts of total gelling polymer can be present in one or morelocations of the dosage form, to achieve the specified total amount,such as in a portion at a coated particle (e.g., core), a matrix (e.g.,compressed matrix) structure that supports and contains the coatedparticles, or in both the coated particles and the matrix.

A core (uncoated) of a core-shell particle can contain any useful amountof gelling polymer, such as from 0 up to and including 100 percentgelling polymer in a core of a core-shell particle, e.g., from 10 to 95weight percent gelling polymer based on a total weight of the core, suchas from 40 to 85 or 50 to 75 weight percent gelling polymer based ontotal weight core.

Described in terms of total weight of a dosage form, an amount ofgelling polymer present in a core of a core shell polymer may be, e.g.,in a range from 0.5 to 15 weight percent gelling polymer (present in thecore) per total weight of the dosage form, such as from 1 to 10 weightpercent gelling polymer (present in the core) per total weight dosageform. An amount of gelling polymer present in a matrix of a dosage formmay be any desired amount, such as an amount in a range from 0.5 to 15weight percent gelling polymer (as excipient in a matrix) based on atotal weight of the dosage form, such as from 1 to 10 weight percentgelling polymer (present as excipient in a matrix) based on total weightdosage form.

A useful gelling polymer can be any polymeric material that exhibits theability to retain a significant fraction of adsorbed solvent in itsmolecular structure, e.g., the solvent being a solvent otherwise usefulby an abuser to extract API from a dosage form or a crushed or powdereddosage form, the solvent for example being water or a C₁ to C₄ alcoholsuch as ethanol or methanol, etc. Examples of gelling polymers includematerials that can swell or expand to a very high degree when placed incontact with such a solvent. The swelling or expansion may cause thegelling polymer to experience from a two- to one-thousand-fold volumeincrease from a dry state. More specific examples of gelling polymersinclude swellable polymers sometimes referred to as osmopolymers orhydrogels. The gelling polymer may be non-cross-linked, lightlycrosslinked, or highly crosslinked. The crosslinking may involvecovalent or ionic bonds with the polymer possessing the ability to swellin the presence of a solvent, and when cross-linked will not dissolve inthe solvent.

A gelling polymer, upon dissolution or dispersion in an aqueous solutionor dispersion (e.g., water) at a concentration of 2% w/w (based on thedry material), creates a solution/dispersion with a viscosity of fromabout 100 to about 200,000 mPa·s (e.g., 4,000 to 175,000 mPa·s, and4,000 to 50,000 mPa·s$) as measured at 20 degrees Celsius (+/−0.2 degreeCelsius) using the analysis method described in the USP 33 monograph forhypromellose (incorporated herein by reference).

Generally suitable gelling polymers include pharmaceutically acceptablepolymers that undergo an increase in viscosity upon contact with asolvent, as described. Various examples of polymers are known to beuseful in this manner, generally including natural and syntheticstarches (i.e., modified or pregelatinized modified starch), natural andsynthetic celluloses, acrylates, and polyalkylene oxides. Examples ofnatural starches include natural starches include corn starch, potatostarch, rice starch, tapioca starch and wheat starch, hydroxypropylstarch such as hydroxypropyl corn starch, hydroxypropyl pea starch andhydropropyl potato starch (derivative of natural starch). Examples ofsynthetic starches, i.e., modified or pregelatinized modified starch,include acetylated distarch adipate, waxy maize basis, acid-treatedmaize starch, acid-treated waxy maize starch, distarch phosphate, waxymaize basis, oxidized waxy maize starch, and sodium octenyl succinatestarch. Examples of celluloses include carboxymethylcellulose calcium,carboxymethylcellulose sodium, ethycellulose, methylcellulose, celluloseethers such as hydroxypropyl cellulose, hydroxyethylcellulose,hydroxyethylmethyl cellulose, hydroxypropyl methyl cellulose,carboxymethylcellulose sodium, and low substituted hydroxypropylcellulose. Examples of acrylates include Eudragit RS, RL, NE, NM.Examples of polyalkylene oxides include polyethylene oxide such asPOLYOX N10, N80, N60K, WSR-1105 LEO, or WSR-301 LEO, or WSR-303 LEO.

Accordingly, examples of suitable gelling polymers include polyethyleneoxide, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropylcellulose, methyl cellulose, hydroxyethylmethylcellulose, sodiumcarboxymethylcellulose, hydroxyethylcellulose, polyacrylic acid andpolyvinyl carboxy polymers such as those commercially available underthe trade name Carbopol®, and other high molecular weight polymerscapable of attaining a viscosity level effective to prevent uptake in asyringe, if combined with a small volume of solvent as described.

Other examples of suitable gelling polymers can include, if ofsufficiently high molecular weight: ethylcellulose, cellulose acetate,cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate and cellulose triacetate, cellulose ether, celluloseester, cellulose ester ether, cellulose; acrylic resins comprisingcopolymers synthesized from acrylic and methacrylic acid esters, forexample acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylicacid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers.

Exemplary gelling polymers can include natural polymers such as thosederived from a plant or animal, as well as polymers preparedsynthetically. Examples include polyhydroalkylcellulose having amolecular weight greater than 50,000; poly(hydroxy-alkylmethacrylate)having a molecular weight of from 5,000 to 5,000,000;poly(vinyl-pyrrolidone) having a molecular weight of from 100,000 to3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes;poly(vinyl alcohol) having a low acetate residual; a swellable mixtureof agar and carboxymethyl cellulose; a swellable composition comprisingmethyl cellulose mixed with a sparingly cross-linked agar; a polyetherhaving a molecular weight of from 10,000 to 6,000,000; water-swellablecopolymer produced by a dispersion of finely divided copolymer of maleicanhydride with styrene, ethylene, propylene, or isobutylene; waterswellable polymer of N-vinyl lactams; and the like.

Other polymers useful as a gelling polymer include pectin having amolecular weight ranging from 30,000 to 300,000; polysaccharides such asagar, acacia, karaya, tragacanth, algins and guar; polyacrylamides;water-swellable indene maleic anhydride polymers; Goodrite® polyacrylicacid having a molecular weight of 80,000 to 200,000; Polyox®polyethylene oxide polymers having a molecular weight of 100,000 to7,000,000; starch graft copolymers; Aqua-Keep® acrylate polymers withwater absorbability of 400 times its original weight; diesters ofpolyglucan; a mixture of cross-linked polyvinyl alcohol andpoly(-vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecularweight of 4,000 to 100,000.

In various specific embodiments, a gelling polymer may be, or mayinclude, hydroxypropyl methyl cellulose (e.g., Hypromellose or HPMC),and hydroxy methyl cellulose, methyl cellulose, hydroxyethylmethylcellulose, and sodium carboxymethyl cellulose. The hydroxypropyl methylcellulose can have a molecular weight ranging from 10,000 to 1,500,000.Examples of suitable, commercially available hydroxypropylmethylcellulose polymers include HPMC K100M, Methocel K100LV andMethocel K4M.

A specific class of gelling polymer is the class of carbomer polymers,which are polymers derived from acrylic acid (e.g., acrylic acidhomopolymers) and crosslinked with polyalcohol allyl ethers, e.g.,crosslinked with polyalkenyl ethers of pentaerythritol or sucrose.Carbomer polymers are hydrophilic and are not substantially soluble inwater. Rather, these polymers swell when dispersed in water forming acolloidal, mucilage-like dispersion. Carboxyl groups provided by acrylicacid residues of the polymer backbone are responsible for certainbehavior of the polymers. Particles of this polymer can be viewed as anetwork structure of polymer chains interconnected by crosslinks. Thestructure can swell in water by up to one thousand times of an original(dry) volume (and ten times an original diameter of polymer particles)to form a gel when exposed to a pH environment above 4-6. The pKa ofthese polymers can be 6±0.5. Accordingly, carboxylate groups pendantfrom the polymer backbone can ionize at a pH above 6, producing arepulsion between the negatively-charged particles, which adds to theswelling of the polymer if exposed to solvent at this pH range. For thisreason, a dosage form as described herein can preferably include a pHadjuster in an amount and location within the dosage form to raise thepH of a carbomer polymer to at least 6, to substantially neutralize thecarboxylate groups.

A suitable amount of a pH adjuster may be from about 1 to about 10millimoles, or from about 5 to about 9 millimoles, or from about 6 toabout 8 millimoles, or from about 7 to about 7.5 millimoles of the pHadjuster per gram of the carbomer polymer that is present in the dosageform. According to some embodiments, a suitable amount of a pH adjustermay be from about 50 to about 400 millimoles; or from about 50 to about350 millimoles; or from about 50 to about 250 millimoles; or from about50 to about 150 millimoles; or from about 50 to about 100 millimoles ofthe pH adjuster per gram of the carbomer polymer that is present in thedosage form. According to other embodiments, a suitable amount of a pHadjuster may be from about 200 to about 400 millimoles; or from about300 to about 400 millimoles of the pH adjuster per gram of the carbomerpolymer. According to certain embodiments, a suitable amount of a pHadjuster may be from about 50 to about 70 millimoles; or about 60millimoles of the pH adjuster per gram of the carbomer polymer.According to certain embodiments, a suitable amount of a pH adjuster maybe from about 300 to about 350 millimoles, or about 310 millimoles ofthe pH adjuster per gram of the carbomer polymer.

According to some embodiments, the pH adjuster is present in a dosageform according to the invention in an amount that is from about 1 toabout 5 percent by weight, or from about 2 to about 4 percent by weight,or about 3 to 4 percent by weight based on the total weight of thedosage form. According to some other embodiments, the pH adjuster ispresent in a dosage form according to the invention in an amount that isfrom about 5 to about 20 percent by weight. According to some of theseembodiments, the pH adjuster is present in an amount that is from about5 to about 15 percent by weight, or from about 10 to about 15 percent byweight based on the total weight of the dosage form; or from about 9 toabout 14 percent by weight. According to certain embodiments, the pHadjuster is present in an amount that is from about 9 to about 11percent by weight; or from about 12 to about 14 percent by weight; orabout 10 percent by weight, or about 13 percent by weight.

Carbomer polymers are often referred to in the art using alternativeterminology such as, for example, carbomer homopolymer, acrylic acidpolymers, carbomer, Carbopol, carboxy polymethylene, carboxyvinylpolymer, Pemulen, polyacrylic acid, and poly(acrylic acid), The USP-NFlists three umbrella monographs i.e. for “carbomer copolymer,” for“carbomer homopolymer,” and for “carbomer interpolymer.”

Certain carbopol (carbomer) polymers that may be useful as a gellingpolymer can have an average equivalent weight of 76 per carboxyl group.Examples of suitable commercially available carbomers include Carbopol®934, 934P NF, Carbopol® 974P NF and Carbopol® 971P NF, Carbopol® 940,and Carbopol® 941, Carbopol® 71G, commercially available from Lubrizol.Examples of such polymers are described in U.S. Pat. Nos. 2,798,053 and2,909,462, the entireties of which are incorporated herein by reference.Theoretical molecular weight ranges of Carbopol® products are in a rangefrom 700,000 to 3 billion, theoretical estimation. For dosage forms asdescribed herein, a gelling polymer (e.g., Carbopol®) can have amolecular weight and viscosity-increasing performance that will reduceor substantially inhibit an ability of an abuser to extract API from acombination of dosage form and a small volume of solvent, as described,while also being capable of being processed into a compressed dosageform.

A gelling polymer can also be characterized by viscosity of a solutionprepared from the gelling polymer. Product information for commerciallyavailable Carbopol® polymers reports that viscosities of differentCarbopol® polymers are as follows:

Viscosity Type of Carbomer specified (cP) Carbomer Homopolymer Type A(compendial name for  4,000-11,000 Carbopol 71G, Carbopol 971P andCarbopol 981) Carbomer Homopolymer Type B (compendial name for25,000-45,000 Carbopol 934P, and Carbopol 934) Carbomer Homopolymer TypeC (compendial name for 40,000-60,000 Carbopol 980) (Type A and Type Bviscosities measured using a Brookfield RVT, 20 rpm, neutralized to pH7.3-7.8, 0.5 weight percent mucilage, spindle #5.)

Another example of a type of preferred gelling polymer is the class ofxanthan gum polymers, which includes natural polymers useful ashydrocolloids, and derived from fermentation of a carbohydrate. Amolecular weight of a Xanthan gum may be approximately 1,000,000.Xanthan gum has been shown to provide particularly useful extractionresistance in a dosage form as described, and therefore may be preferredin dosage forms as described, especially if present in an amount of atleast 2 or 3 weight percent based on a total weight of a dosage form.

Without limiting the scope of useful gelling polymers to any specifictype or molecular weight, examples of useful gelling polymers, anduseful respective molecular weights, are shown at Table below.

Gelling Polymer Weight Average Molecular Weight Carbomer 700,000 to 3billion (estimated) HPMC 2910 K types 164,000-1,200,000 HPMC 2910 Etypes 20,000-746,000 hydroxyethylcellulose   90,000-1,300,000ethylcellulose 75,000-215,000 carboxymethylcellulose 49,000-725,000sodium carboxymethylcellulose 49,000-725,000 povidone   4,000-1,300,000copovidone 47,000 hydroxypropyl cellulose   40,000-1,150,000 xanthan gum1,000,000 polyethylene oxide Average molecular wt: 100,000-7,000,000

The dosage form may optionally include another abuse deterrent in theform of a wax, such as a wax/fat material as described in Applicant'sco-pending United States patent application 2008/0311205, the entiretyof which is incorporated herein by reference. The wax can be a solid waxmaterial that is present in the dosage form at a location that inhibitsan abuser from crushing, grinding, or otherwise forming the dosage forminto a ground powder that might be abused by a nasal insufflation mode,or from which active pharmaceutical agent can be easily accessed andremoved such as by dissolution or extraction using a solvent.

The wax may be present in the dosage form at a location and in an amountto also not interfere with desired uptake of the active pharmaceuticalingredient by a patient upon oral ingestion, in an immediate releasedosage form. An exemplary location is at a core of a core-shellparticle, especially a core that also contains gelling polymer and thateither may or may not contain active pharmaceutical ingredient. Waxlocated at a core of a particle (e.g., a core-shell particle) that alsoincludes active pharmaceutical ingredient (e.g., at a layer covering thecore, or within the core) will become mixed with the activepharmaceutical ingredient upon crushing or grinding, etc., of theparticle. As discussed previously, the dosage form may also include coreshell particles that do not contain an API. Wax that is located at acore of such a particle (e.g., a core-shell particle) that does notcontain API will also become mixed with the API (e.g., API present inAPI-containing core shell particles that are also present in the dosageform) upon crushing, grinding, etc., of the dosage form. When the wax ismixed with the active pharmaceutical ingredient, the active ingredientis inhibited or prevented from becoming thereafter dissolved in asolvent such as water, or otherwise efficiently accessed by an abuser.

A core (uncoated) of a core-shell particle can contain any useful amountof wax, up to and including 100 percent wax, e.g., from 0.1 to 85 weightpercent wax based on a total weight of the core, such as from 15 to 60or 25 to 50 weight percent wax based on total weight core. Moregenerally, a useful amount of wax in a dosage form (e.g., with the waxlocated in the coated particle, e.g., in the core) may be in a rangefrom 0.05 to 15 weight percent wax based on total weight of a dosageform, e.g., from 0.1 to 10 or from 2 to 5 weight percent wax based ontotal weight of the dosage form.

The wax may be a wax (e.g., fat) material that is generally hydrophobicand that may be either solid or liquid at room temperature, preferablysolid at room temperature (25 degrees Celsius). Generally useful fatsinclude those hydrophobic materials that are fatty acid-based compoundsgenerally having a hydrophilic/lipophilic balance (HLB) of 6 or less,more preferably 4 or less, and most preferably 2 or less. A fat can haveany melting temperature, with preferred fats being solid at roomtemperature and having a melting point that is at least 30 degreesCelsius, e.g., at least 40 degrees Celsius, e.g., at least 50 degreesCelsius. Useful fats include fatty acids and fatty esters that may besubstituted or unsubstituted, saturated or unsaturated, and that have achain length of at least 10, 12, or 14 carbons. The esters may include afatty acid group bound to any of an alcohol, glycol, or glycerol. Withregard to glycercols, for example, mono-, di-, and tri-fatty substitutedglycerols can be useful as well as mixtures thereof.

Suitable wax ingredients include fatty acid esters, glycerol fatty acidesters, fatty glyceride derivatives, waxes, and fatty alcohols such as,for example, glycerol behenate (a.k.a. glyceryl behenate, glycerinbehenate, glycerol docosanoate) (e.g., COMPRITOL®), glycerolpalmitostearate (PRECIROL®), glycerol monostearate, stearoylmacroglycerides (GELUCIRE® 50/13). Other waxes more generally includeinsect and animal waxes, vegetable waxes, mineral waxes, petroleumwaxes, and synthetic waxes; particularly examples include beeswax,carnauba wax, candelilla wax, montan wax, ouricury wax, rice-bran wax,jojoba wax, microcrystalline wax, cetyl ester wax, cetyl alcohol,anionic emulsifying wax, nonionic emulsifying wax and paraffin wax.

The dosage form may optionally include another abuse deterrent in theform of a filler or binder material provided in a manner to compromisingabuse practices wherein an abuser crushes, grinds, or otherwise formsthe dosage form into a ground powder that might be abused by a nasalinsufflation mode, or from which active pharmaceutical agent can beeasily accessed and removed such as by dissolution or extraction using asolvent.

The binder or filler may be present in the dosage form at a location andin an amount to also not interfere with desired uptake of the activepharmaceutical ingredient by a patient upon oral ingestion, in animmediate release dosage form. An exemplary location is at a core of acore-shell particle. Suitable filler or binder located at a core of aparticle (e.g., a core-shell particle) that also includes activepharmaceutical ingredient (e.g., at a layer covering the core, or withinthe core) will become mixed with the active pharmaceutical ingredientupon crushing or grinding, etc., of the particle. As discussedpreviously, the dosage form may also include core shell particles thatdo not contain an API. Filler or Binder that is located at a core ofsuch a particle (e.g., a core-shell particle) that does not contain APIwill also become mixed with the API (e.g., API present in API-containingcore shell particles that are also present in the dosage form) uponcrushing, grinding, etc., of the dosage form. When a filler or binder ismixed with the active pharmaceutical ingredient, the activepharmaceutical ingredient is inhibited or prevented from becomingthereafter dissolved in a solvent such as water or otherwise efficientlyaccessed by an abuser.

When present within a core or particle of a dosage form, e.g., at a coreof a core-shell particle, filler or binder may be present in any usefulamount, such as from 0 up to and including 100 percent filler or binder(singly or in combination) in a core of a core-shell particle, e.g.,from 10 to 95 weight percent filler or binder (singly or in combination)based on total weight of the core, such as from 40 to 85 or 50 to 75weight percent based on total weight core. Examples of cores thatcontain high levels of filler include spherical particles that contain100 percent sugar, and spherical particles that contain 100 percentmicrocrystalline cellulose. Inert spherical filler products such asthese, having useful particle sizes, are commercially available underthe trade name Celphere®, and under the trade name Suglets® (sugarspheres, also containing starch), including as follows: CELPHERE SCP-100(Particle size (μm) 75-212); CELPHERE SCP-102 (Particle size (μm)106-212); CELPHERE SCP-203 (Particle size (μm) 150-300); CELPHERESCP-305 (Particle size (μm) 300-500); CELPHERE SCP-507 (Particle size(μm) 500-710); CELPHERE SCP-708 (Particle size (μm) 710-850). Theparticle sizes of these can be considered to be useful for any core asdescribed herein, prepared of any single filler, gelling polymer,binder, any combination thereof, or any single or combination ofmaterials combined with API.

Another optional abuse deterrent feature that can be included in adosage form as described is a film layer or coating as part of acore-shell particle that is located over and surrounds an API. The filmlayer may also be present as a layer or coating on core shell particleswhich do not contain an API or an API layer. The film layer can be anyfilm layer capable of being applied as a film layer to core-shellparticles, to surround API, or to core-shell particles that do notcontain an API or an API layer.

The film layer may be prepared from, and will include anypharmaceutically acceptable film forming polymer material, such as oneor more of a binder (e.g. as described herein, such as hydroxypropylcellulose, poly(methyl methacrylates), ethyl cellulose, hydroxypropylmethyl cellulose, hydroxyl methyl cellulose, polyvinyl alcohol, and thelike), a solvent-resistant layer, and a pH-sensitive layer (alsosometimes referred to as a reverse enteric material or layer), e.g.,Eudragit® E 100. The film layer may include any one of these materialsalone (e.g., a film layer may include 100 percent of a single one ofthese types of materials), or a film layer may include a combination oftwo or more of these types of materials.

A solvent-resistant layer is a film layer that retards or preventrelease of a drug in a solvent (e.g., one or more of water, ethanol, andmethanol) while still allowing the drug to release normally in agastrointestinal tract when ingested as an immediate release oral dosageform. This type of abuse deterrent feature, e.g., solvent-resistantfilm, can inhibit access to an API of a dosage form by preventing orimpeding an abuser from dissolving an intact or powdered dosage form ina solvent type that is often used by an abuser (e.g., water, ethanol,methanol). At the same time, the solvent-resistant film can dissolve ina human gastrointestinal tract with sufficient rapidity to allow for animmediate release profile. As an abuse deterrent feature this type ofsolvent-resistant film covers and encloses API of a core-shell particleand acts as a film barrier or retardant to prevent or retard access tothe API by use of solvent.

A solvent-resistant film is one that does not readily or immediatelydissolve in a small volume of a solvent of the type often used by anabuser to dissolve an API, such as any one of water or a C₁-C₄ alcoholsuch as ethanol or methanol. A “small volume” refers to an amount ofsuch a solvent that can contain an amount of dissolved API that issufficiently concentrated to be useful to an abuser to realize theintended biological effect of the drug abuse, and that is also capableof being administered for abuse of the API, e.g., a volume that cancontain an amount (concentration) of API that is effective to achieve adesired “high” if administered by injection or nasal insufflation, thevolume also being sufficiently small to allow the volume to beadministered by injection or nasal insufflation. For a dosage form to beuseful for abuse as such, an API in the dosage form must be capable ofbeing accessed and dissolved at sufficient concentration by an abuserwithout undue complication, into a “small volume” of solvent, which is avolume that can be administered by injection or by nasal insufflation.Generally, a “small volume” of solvent means 50 milliliters or less, or20 milliliters or less, or 10 milliliters or less, or 5 milliliters orless (volumes which could be injected or used for nasal insufflation).

A solvent-resistant film layer can be a film placed on a core-shellparticle that is difficult to dissolve in a “small volume” of water or aC₁-C₄ alcohol such as ethanol or methanol, e.g., that does notimmediately dissolve in one or more of water or any one of a C₁-C₄alcohol such as methanol or ethanol. The solvent-resistant film therebyretards or prevents an abuser from accessing an API portion of acore-shell particle if the core-shell particle is placed in one of thesesolvents. The solvent-resistant film need not be completely orsubstantially insoluble in any one of these solvents, or in all of thesolvents, and it must be capable of allowing the API to be accessed withsufficient rapidity, in a gastrointestinal tract, for the dosage form tobe useful as an immediate release dosage form.

A particular example of a solvent-resistant film is a film that exhibitssolubility properties that depend on the pH of a solvent. An example ofa solvent-resistant film may be a film that is substantially orcompletely insoluble at a pH that is greater than a pH condition of ahuman stomach, and that is sufficiently soluble at a pH condition of astomach (and gastrointestinal tract) to allow the film to dissolve andrelease API with sufficient rapidity that the dosage form can be usefulas an immediate release oral dosage form. A pH-sensitive layer is a typeof solvent-resistant film, and can be disposed in a dosage form tosurround an active pharmaceutical ingredient and inhibit or preventaccess to and dissolution of the active pharmaceutical ingredient in asolvent outside of a stomach (e.g., at a neutral pH environment), whilestill allowing the active pharmaceutical ingredient to be efficientlyreleased from an immediate release dosage form at a lower pH environmentof a user's stomach. This type of abuse deterrent feature can prevent orsignificantly impede an abuser's access to an active pharmaceuticalagent of a dosage form (e.g., at the core of a core-shell particle or ina layer disposed on the core, or in both the core and the layer disposedon the core) by use of a solvent that is outside of a stomach and thatdoes not have a relatively acidic pH, such as water or a C₁-C₄ alcoholsuch as ethanol, methanol, etc., or a mixture thereof, having a pH thatis higher than a pH found in a human stomach, for example a pH greaterthan 4; greater than 5; or greater than 5.5; or greater than 6.

A pH-sensitive layer may be useful as a solvent-resistant film, placedin a dosage form as a layer of a core-shell particle to surround, cover,or enclose a portion of the core-shell particle that contains activepharmaceutical ingredient. For example in a core-shell particle, anactive pharmaceutical ingredient may be located as desired at a core orat a layer outside of an uncoated or coated core; a solvent-resistantfilm in the form of a pH-sensitive layer may be disposed as a separatelayer surrounding or covering the portion of the core-shell particlethat contains the active pharmaceutical ingredient. The pH-sensitivelayer may be in direct contact with (adjacent to) a core or a layer thatincludes active pharmaceutical ingredient; alternately a core-shellparticle may include one or more intermediate layers between apH-sensitive layer and a core or layer that includes activepharmaceutical ingredient. In addition, a pH-sensitive layer may beincluded in the dosage form as a layer of a core-shell particle thatdoes not contain either an API layer or any API.

A useful pH-sensitive layer may include a polymer or other material thatcan be placed as a layer of a particle as described herein, such as tocover a more inner layer or core that contains active pharmaceuticalingredient, to form a pH-sensitive film surrounding or covering activepharmaceutical ingredient. The pH-sensitive film can be solubilized byexposure to a liquid that exhibits a pH that may be present in a stomachof a user of the dosage form, such as a pH below 6 or below 5.5. Tofunction as an abuse deterrent feature, i.e., to inhibit or preventefficient access to the active pharmaceutical ingredient by exposing thedosage form (optionally ground or powdered) to an easily-availablesolvent, the pH-sensitive layer can contain polymer that is not easilyor substantially soluble at a pH that is higher than a pH found in ahuman stomach, e.g., a pH greater than 6; by being insoluble at a pHgreater than 6, the pH-sensitive polymer will not dissolve in manysolvents easily available and commonly used by an abuser to extract awater-soluble drug from a dosage form such as water, ethanol, methanol,etc.

Examples of pH-sensitive polymer useful in a pH-sensitive layer includethe class of reverse enteric polymers that contain cationic-functionalgroups and that exhibit pH-dependent solubility as described herein.Examples include polymers that contain basic functional groups such asamino groups, and that exhibit solubility at pH conditions found in a(human) stomach but not at relatively higher pH conditions, e.g., notabove a pH of 4, 5, or 5.5, or not above a pH of 6. More specificexamples of such pH-sensitive polymers include copolymers of dimethylaminoethyl methacrylates, and neutral methacrylic acid esters; e.g.,dimethyl aminoethyl methacrylate, butyl methacrylates, and methylmethacrylates, such as at a ratio of 2:1:1. Examples of such polymersare commercially available under the trade name Eudragit® E-100,Eudragit® E PO, Eudragit® E 12.5, and similar amino-functionalpH-sensitive polymers. A preferred pH-sensitive polymer is the polymerEudragit E100, but any polymer that is sufficiently hydrophilic at a lowpH and hydrophobic at a higher pH to exhibit pH-dependent solubility asdescribed, may also be effective if otherwise acceptable for use in apharmaceutical dosage form, for example as a non-toxic ingredient of anoral dosage form. Reverse enteric compositions are also described in EP1694724 B1, titled “pH Sensitive Polymer and Process for PreparationThereof.”

When present as a coating of a particle that contains activepharmaceutical ingredient, a solvent-resistant film layer may be presentat any amount useful as an abuse deterrent feature, such as in a rangefrom 0.1 to 90 weight percent of a total weight of a core-shellparticle, e.g., from 3 to 50 or 4 to 40 weight percent solvent-resistantpolymer per total weight core-shell particle. More generally, a usefulamount solvent-resistant film layer or polymer in a dosage form may bein a range from 1 to 50 weight percent solvent-resistant film layer orpolymer based on a total weight of a dosage form, e.g., from 2 to 30 orfrom 3 to 15 weight percent solvent-resistant polymer based on totalweight dosage form. Similarly, when present as a coating of a particlethat does not contain an API, a solvent-resistant film layer may bepresent at any amount useful as an abuse deterrent feature, for examplein the same numerical ranges as are disclosed above for coatingparticles that contain API.

A dosage form as presently described can also preferably include adisintegrant, which functions to cause the dosage form to expand andbreak up during use, e.g., at conditions of a human stomach, to allowactive pharmaceutical ingredient of the dosage form to be released in amanner to achieve an immediate release profile. Disintegrants are knowningredients of pharmaceutical dosage forms, with various examples beingknown and commercially available. Examples of disintegrants includecompositions of or containing sodium starch glycolate, starch (e.g.,maize starch, potato starch, rice starch, tapioca starch, wheat starch,corn starch and pregelatinized starch), croscarmellose sodium,crospovidone (crosslinked polyvinyl N-pyrrolidone or PVP) (polyplasdoneXL-10), sodium starch glycolate (EXPLOTAB® or PRIMOJEL®), anycombination of two or more of the foregoing, and other pharmaceuticallyacceptable materials formed into particles having a particle size,density, etc., to allow processing of the disintegrant into a usefulimmediate release dosage form.

The disintegrant can be present in an immediate release dosage form atany location that allows the disintegrant to function as desired, toexpand within the intact dosage form, upon ingestion, to cause theingested dosage form to break apart and allow for desired immediaterelease of active pharmaceutical ingredient from the dosage form, in astomach. One useful location for a disintegrant can be as a component ofan excipient used to contain core-shell particles that contain activepharmaceutical ingredient, as described herein, in a dosage form such asa compressed tablet or capsule.

When included as an excipient of a dosage form, disintegrant may bepresent in an amount useful to achieve immediate release of an API of adosage form. Examples of useful amounts of disintegrant in an immediaterelease dosage form as described herein may be in a range from 0.5 to 50weight percent disintegrant based on a total weight of the dosage form,e.g., from 1 to 30 weight percent disintegrant based on total weight ofthe dosage form. The amount of disintegrant in a matrix of a dosage formcan be consistent with these amounts, e.g., disintegrant can be includedin a matrix (e.g., total of a dosage form that is other than the coatedparticles or API) of a dosage form in an amount in a range from 0.5 to50 weight percent disintegrant based on a total weight of the matrix,e.g., from 1 to 30 weight percent disintegrant based on total weightmatrix.

A dosage form as described can also include any of various known andconventional pharmaceutical excipients that may be useful to achievedesired processing and performance properties of an immediate releasedosage form. These excipients include fillers, binders, lubricants,glidants, coloring agents, pH-adjusters, etc., and can be included incore-shell particles or in a matrix (e.g., compressed matrix) of atablet or capsule. A more detailed description of pharmaceuticalexcipients that may also be included in the tablets of the presentinvention can be found in The Handbook of Pharmaceutical Excipients, 5thed. (2006).

A pH-adjuster can be included in an immediate release dosage form asdescribed, for example at a location to affect pH at a specific locationof the dosage form that is only a portion of a total dosage form. As anexample, a pH-adjuster in the form of a base may be included at alocation of a gelling polymer that contains acid functionalities, toneutralize the acid functionalities. Suitable agents that can act as apH-adjuster are well know in the art and include for example, phosphatebuffering agents such as, disodium hydrogen phosphate, sodium dihydrogenphosphate and the equivalent potassium salts; carbonate or bicarbonatesalts, such as sodium bicarbonate, sodium carbonate, potassiumbicarbonate, potassium carbonate, magnesium carbonate and calciumcarbonate; hydroxide bases such as, sodium hydroxide, potassiumhydroxide, ammonium hydroxide; and amine bases such as, triethanolamine,tromethamine, aminomethyl propanol, and tetrahydroxypropylethylenediamine.

The amount of pH-adjuster included at the location of the gellingpolymer can be an amount effective to neutralize the acidfunctionalities of the gelling polymer at that location. Morespecifically, a component of a dosage form as described that includes anacid-functional gelling polymer such as a carbopol may include a base inan amount and location to neutralize the acid functionalities of thatpolymer. The pH-adjuster can be located at a location effective to causesuch neutralization, e.g., at the location of the dosage form thatcontains the acid-functional gelling polymer, for example at a core of acore-shell particle or as part of an excipient that includesacid-functional gelling polymer and that functions to bind particlestogether as a dosage form.

Examples of fillers that may be useful in an immediate release dosageform as described include lactose, starch, dextrose, sucrose, fructose,maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose,powdered cellulose, calcium sulfate, calcium phosphate, dicalciumphosphate, lactitol or any combination of the foregoing. As compared tonon-filler ingredients such as gelling polymers, a filler will have amolecular weight that does not result in a substantial viscosityincrease or formation of a gel as described herein for a gellingpolymer, if combined with a solvent such as water.

A filler may be present in any portion of a dosage form as described,including a core-shell particle; the filler may be present in a core, ina layer containing an active pharmaceutical ingredient that is disposedon the core, in a solvent resistant film, in the matrix, or in two ormore of these portions of the dosage form. The filler may be present atany one or more of these portions of a dosage form in an amount toprovide desired processing or functional properties of a portion of thedosage form and of the entire dosage form. The amount of total filler ina dosage form can also be as desired to provide desired functionality,including an immediate release profile, for example in an amount in arange from 0 to 80 weight percent filler based upon the total weight ofthe dosage form, e.g. from 5 to 50 percent filler based on total weightdosage form.

Examples of binders that may be included in a dosage form as describedinclude polymeric material such as alginic acid, sodiumcarboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, starch, pregelatinized starch, polyvinylalcohol, polyethylene oxide, polyvinylpyrrolidone, polyacrylamides,polyvinyloxoazolidone, polyvinylalcohols, methylcellulose, hydroxypropylcellulose, hydroxymethyl cellulose and any combination of two or more ofthese. A binder may be a water soluble material; as compared tonon-binder ingredients such as a gelling polymer, a binder is of amolecular weight that does not result in formation of a gel or a highlyviscous composition upon combining with a small volume of water. Abinder can exhibit a relatively low molecular weight as compared to agelling polymer, and a relatively lower viscosity (e.g., when measuredin a 2% aqueous solution). Polymer useful as a binder may typically havea molecular weight of less than 50,000, e.g., less than 30,000, or lessthan 10,000.

A binder may be present in any portion of a dosage form as described,including a core or a film or coating of a core-shell particle, or aspart of an excipient to contain or bind core-shells particles in adosage form. Filler may be included in a core of a core-shell particlein combination with active pharmaceutical ingredient, gelling polymer orboth; as part of an active pharmaceutical layer located over a core oranother layer of a core-shell particle; as part of a solvent-resistantfilm; or within an excipient useful to bind particles into a dosageform. A binder may be present at any one or more of these portions of animmediate release dosage form as described, in an amount to providedesired processing or functional properties in each portion of thedosage form and of the overall dosage form. The amount of total binderin a dosage form can also be as desired to provide desiredfunctionality, including immediate release functionality. For example abinder may be provided in an amount in a range from 0.1 to 10 weightpercent binder based on a total weight of a dosage form, e.g., from 0.5to 7 weight percent binder based on total weight dosage form. Accordingto some embodiments, the binder may be provided in amounts ranging from0.1 to 25, or 0.1 to 40 weight percent based on a total weight of adosage form.

Examples of lubricants include inorganic materials such as talc (ahydrated magnesium silicate; polymers, such as, PEG 4000; fatty acids,such as stearic acid; fatty acid esters, such as glyceride esters (e.g.,glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate);sugar esters (e.g., sorbitan monostearate and sucrose monopalmitate);glyceryl dibehenate (Compritol® 888 ATO); and metal salts of fatty acids(e.g., magnesium stearate, calcium stearate, and zinc stearate).Accordingly, commonly used lubricants include talc, glycerylmonostearates, calcium stearate, magnesium stearate, stearic acid,glyceryl behenate, polyethylene glycol, poloxamer and combinations ofthe foregoing. Lubricant may be included in an immediate release dosageform as described, in any useful amount, such as an amount in a rangefrom 0.1 to 10 weight percent lubricant based on a total weight of adosage form, e.g., from 0.5 to 7 weight percent lubricant based on totalweight dosage form.

Examples of glidants include colloidal silicon dioxide, untreated fumedsilica (e.g., as available under the trade name Cab-O-Sil®), andcrystalline or fused quartz. Glidant may be included in an immediaterelease dosage form as described, in any useful amount.

Examples of coloring agents include FD&C-type dyes and lakes, fruit andvegetable extracts, titanium dioxide, iron oxides and mixtures thereof.A coloring agent may be incorporated into a dosage form by blending(e.g., co-milling and blending) the coloring agent with any otheringredient. Alternately, coloring agent may be applied to an outersurface of a dosage form.

Any active pharmaceutical ingredient alone or in combination can beincluded in an immediate release dosage form as described herein. Withabuse deterrent features as described herein, some being operative basedon specific structural or compositional features of a core-shellparticle, APIs that can be particularly useful can be those types ofactive pharmaceutical ingredients that can be subject to abuse,addiction, overdosing, or two or more of these; such APIs can be locatedin the dosage form at a location to cause the API to be subject to abusedeterrent features of the core-shell particle, e.g., at a core or innerlayer of a core-shell particle.

Drugs commonly susceptible to abuse include sedative-hypnotics,stimulants (e.g., central nervous system ((CNS) stimulants),anxiolytics, antipsychotics, dissociative anesthetics, and narcoticanalgesics including but not limited to drugs that can causepsychological or physical dependence on the drug. An API can include anytherapeutically acceptable drug salt, drug derivative, drug analog, drughomologue, or polymorph of an active pharmaceutical ingredient.

Sedative hypnotics include, for example, barbiturates, for examplephenobarbital, methobarbital, amobarbital, pentobarbital, butalbital andsecobarbital and pharmaceutically acceptable salts thereof;benzodiazepines, for example diazepam, chlorodiazepoxide, lorazepam,triazolam, temazepam, alprazolam and flurazepam and pharmaceuticallyacceptable salts thereof; phenothiazines, such as for example,alimemazine, chlorpromazine, thioridazine, and pharmaceuticallyacceptable salts thereof, and sleep medications, such as for example,zolpidem, zaleplon, and eszopiclone and pharmaceutically acceptablesalts thereof. Anxiolytics include, for example, benzodiazepines, forexample diazepam, chlordiazepoxide, estazolam, lorazepam, triazolam,alprazolam, clonazepam and flurazepam and pharmaceutically acceptablesalts thereof. CNS stimulants include, for example, amphetamines, suchas for example, dextroamphetamine, levoamphetamine (benzadrine),methamphetamine (methadrine), pseudoephedrine, and Adderall (amphetaminemixed salts) and pharmaceutically acceptable salts thereof, andnon-amphetamine psychostimulants such as methylphenidate, modafinil andarmodafinil and pharmaceutically acceptable salts thereof. Narcoticanalgesics include opioids such as, for example, buprenorphine,butorphanol, cebranopadol, codeine, dihydrocodeine, dihydromorphine,hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, methadone,fentanyl, meperidine, tramadol, propoxyphene, and pharmaceuticallyacceptable salts thereof. Antipsychotic agents can include, for example,phenothiazines as listed above, butyrophenones, such as, for example,droperidol and haloperidol, dibenzoxazepines such as loxapine, andatypical antipsychotic agents such as aripiprazole, clozapine,olanzapine, quetiapine, risperidone ziprasidone, paliperidone andremoxipride.

Other specific drugs which may be susceptible to abuse include forexample, muscle relaxants such as for example cyclobenzaprine andpharmaceutically acceptable salts thereof, cannabinols (e.g.,Δ¹-cannabidiol. Δ²-cannabidiol, Δ³-cannabidiol, Δ^(3,7)-cannabidiol,Δ⁴-cannabidiol, Δ⁵-cannabidiol, and Δ⁶-cannabidiol); cannabinoids, suchas dronabinol, delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD),nabilone, dexanabinol, ajulemic acid, cannabinor, rimonabant andtaranabant, and pharmaceutically acceptable salts thereof; anddissociative anesthetic agents such as ketamine and Esketamine (whichare also known to demonstrate activity in the treatment of depression),and pharmaceutically acceptable salts thereof.

The API's described herein as suitable for formulation according to theinvention are also intended to include such API's wherein the molecularstructures include isotopes of carbon, hydrogen and nitrogen atomsoccurring on those structures. Isotopes include those atoms having thesame atomic number but different mass numbers. For example, isotopes ofhydrogen include deuterium. Isotopes of carbon include C-13. Isotopes ofnitrogen include N-15.

Accordingly, within the chemical structure of any API taught in thisapplication as suitable for the formulations disclosed herein:

-   -   any hydrogen atom or group of hydrogen atoms, could suitably be        replaced by an isotope of hydrogen, i.e., deuterium;    -   any carbon atom or group of carbon atoms, could suitably be        replaced by an isotope of carbon, i.e., ¹³C; and    -   any nitrogen atom or group of nitrogen atoms, could suitably be        replaced by an isotope of nitrogen, i.e., ¹⁵N.

As used herein, an API that is termed “isotopically-enriched” means thatthe abundance of deuterium, ¹³C, or ¹⁵N at any relevant site of thecompound is substantially more than the abundance of deuterium, ¹³C, or¹⁵N naturally occurring at that site in an amount of the compound. Arelevant site in a compound as used above is a site which would bedesignated as “H” or “C” or “N” in a chemical structure representationof the compound when not enriched. The expression, “Naturallyoccurring,” as used above refers to the abundance of the particular atomwhich would be present at a relevant site in a compound if the compoundwas prepared without any affirmative synthesis step to enrich theabundance of a different isotope. Thus, for example in a“deuterium-enriched” compound, the abundance of deuterium at anyrelevant site in the chemical structure of the API can range from anamount that is substantially more than the natural abundance ofdeuterium (about 0.0115%) all the way up to 100%, for example, fromabout 1% to about 100%, or from about 10% to about 100%, or from about50% to about 100%, or from about 90% to about 100%.

Similarly, for a “¹³C-enriched” compound, the abundance of ¹³C at anyrelevant site in the chemical structure of the API can range from anamount that is substantially more than the natural abundance of ¹³C(about 1.109%) all the way up to 100%, for example, from about 5% toabout 100%, or from about 10% to about 100%, or from about 50% to about100%, or from about 90% to about 100%. Similarly for a “¹⁵N-enriched”compound, the abundance of ¹⁵N at any relevant site in the chemicalstructure of the API can range from an amount that is substantially morethan the natural abundance of ¹⁵N (about 0.364%) all the way up to 100%,for example, from about 1% to about 100%, or from about 10% to about100%, or from about 50% to about 100%, or from about 90% to about 100%.

Isotopically-enriched compounds can generally be prepared byconventional techniques known to those skilled in the art. Suchisotopically-enriched compounds can also be prepared by adaptingconventional processes as described in the scientific literature forsynthesis of API's disclosed herein as suitable for formulationaccording to the invention, and using an appropriateisotopically-substituted reagent (or reagents) in place of thecorresponding non isotopically-substituted reagent(s) employed in theconventional synthesis of the non isotopically-enriched compounds.Examples of ways to obtain a deuterium-enriched compound includeexchanging hydrogen with deuterium or synthesizing the compound withdeuterium-enriched starting materials.

The amount of active pharmaceutical ingredient included in an immediaterelease dosage form can be any useful amount, as is known and as may befound in relevant literature such as Goodman & Gillman's, ThePharmacological Basis of Therapeutics, 9th ed. pages 219-222, 361-396,521-535 1996. For example, typical therapeutic amounts of oxycodonerange 5 mg, 10 mg, or up to 400 mg, for the hydrochloride salt. Often,when processed into a suitable immediate release dosage form, the activepharmaceutical ingredient can be present in such dosage form in anamount normally prescribed, typically 0.5 to 25 percent on a dry weightbasis, based on the total weight of the dosage form. With respect tonarcotic analgesics such as opioids in a single unit dosage form, suchas at a level from about 1 to about 500 mg, or from about 1 to about 250mg, or from about 1 to about 100 mg; for example, 2.5, 5, 7.5, 10, 15,20, or 30, milligram (mg) per dosage form unit. In other embodiments, adosage form contains any appropriate amount of an API to provide atherapeutic effect.

The present invention is also directed to methods of treatment,comprising orally administering an effective amount of the hereindescribed immediate release abuse deterrent dosage form. For example,provided herein is a method of treating or preventing pain or discomfortin a subject in need thereof by administering an effective amount of theherein described immediate release abuse deterrent dosage formcontaining an API that is a narcotic analgesic drug such as an opioiddrug.

Also provided herein is a method for treating sleep disorders in asubject in need thereof by administering an effective amount of theherein described immediate release abuse deterrent dosage formcontaining an API that is a sedative hypnotic drug such as abarbiturate.

Also provided herein is a method for treating anxiety in a subject inneed thereof by administering an effective amount of the hereindescribed immediate release abuse deterrent dosage form containing anAPI that is an anxiolytic drug e.g., a benzodiazepine.

Also provided herein is a method for treating psychoses in a subject inneed thereof by administering an effective amount of the hereindescribed immediate release abuse deterrent dosage form containing anAPI that is an antipsychotic drug such as quetiapine.

Also provided herein is a method for treating depression in a subject inneed thereof by administering an effective amount of the hereindescribed immediate release abuse deterrent dosage form containing anAPI that demonstrates antidepressant activity, such as ketamine orEsketamine.

An “effective amount” of when used in connection with compositiondescribed herein is an amount sufficient to produce a therapeutic resultin a subject in need thereof. For example a therapeutic result caninclude, but is not limited to treating or preventing pain, sleepdisorders, anxiety or psychotic symptomology by a subject.

A dosage form as described can optionally include one or more additionalAPIs of a type that is not commonly susceptible to abuse. Theseadditional APIs may be any suitable or desired API, such as those in theclass of non-steroidal analgesic drugs. The expression “non-steroidalanalgesic drugs” as used herein refers to drugs that include thosecommonly referred to as non-steroidal anti-inflammatory drugs, or“NSAIDS,” and acetaminophen, which is non-steroidal, but does not actvia an inflammation mechanism. Accordingly, the term “non-steroidalanalgesic drugs” would include acetaminophen, and also include NSAIDSsuch as aspirin, ibuprofen, and naproxen. The dosage form also exhibitsimmediate release properties with respect to thesenot-commonly-subject-to-abuse APIs. And these APIs can be present in thedosage form at any useful level, typically 0.5 to 25, e.g., 1 to 10weight percent of the API on a dry weight basis, based on a total weightof the dosage form, e.g., at a level of or between 5, 25, 50, 75, 100,125, 150, 175, 200, 300, 325, 500, 750 or up to or exceeding 1000milligram (mg) per dosage form unit. In other embodiments, a dosage formcontains an appropriate amount of an API to provide a therapeuticeffect.

An immediate release dosage form as described can include one or more ofthe described abuse deterrent features, alone or in combination; e.g.,one or more of: gelling polymer as part of a core-shell particle (e.g.,at a core of the core-shell particle); wax as part of a core-shellparticle (e.g., at a core of the core-shell particle); binder or filleras part of a core-shell particle (e.g., at a core of the core-shellparticle); a film layer that may optionally be a solvent-resistant film(e.g., pH-sensitive film) as part of a core-shell layer; or gellingpolymer as a component of an excipient or binder used to hold core-shellparticles together as part of in an immediate release dosage form. Withthese abuse deterrent features, other types of known abuse deterrentfeatures may not be necessary and may be specifically excluded from animmediate release dosage form as described. Certain embodiments of thedescribed dosage forms can specifically exclude other types of abusedeterrents.

In specific, some dosage forms include nasal irritant to discourage orprevent abuse by nasal insufflation. The nasal irritant can be a mucousmembrane irritant or nasal passageway irritant that, if inhaled througha nasal passageway when contained in a ground or powdered dosage form,can induce pain or irritation of the abuser's nasal passageway tissue.Examples include surfactants such as sodium lauryl sulfate, poloxamer,sorbitan monoesters, and glyceryl monooleates. Certain particularembodiments of dosage forms of the present description do not require,and can specifically exclude, nasal irritant agents such as thosedescribed above.

Alternately, dosage forms can include an emetic agent, to causevomiting. Certain particular embodiments of dosage forms of the presentdescription do not require and can specifically exclude an emetic agent.

Alternately, some dosage forms include an effervescent agent that actsas a deterrent to abuse by nasal insufflation. The effervescent includesan acidic component and a basic component that release a gas such asoxygen or carbon dioxide when combined in the presence of an aqueousmedia, such as upon nasal insufflation. See, e.g., patent publication WO2013/077851, the entirety of which is incorporated herein by reference.The acid source may be, for example, citric acid, tartaric acid, malicacid, maleic acid, lactic acid, glycolic acid, ascorbic acid, fumaricacid, adipic acid, succinic acid, salts thereof, and combinationsthereof. The base may be, for example, a carbonate or bicarbonate.Dosage forms of the present description do not require, and canspecifically exclude, an effervescent agent in the form of an acid and abase that can combine to a gas such as oxygen or carbon dioxide.

Still other dosage forms include a biologically active chemical compoundthat functions as an antagonist to an active pharmaceutical ingredient.An antagonist may prevent the potential abuse of a dosage form in amanner, including the method of consuming multiple or several or moredosage form units at once. Antagonist agents are compounds that block ornegate the effect of an active pharmaceutical ingredient, and areavailable and known for various classes of drugs including opioids andother pharmaceutical agents. Examples of antagonist agents for opioidsinclude compounds such as naltrexone, naloxone, nalmefene, cyclazacine,levallorphan. Specific examples of antagonist agents and methods forpreparing antagonist agents for incorporation into a dosage form areprovided in U.S. Pat. Nos. 7,682,633 and 7,658,939, which areincorporated herein by reference. According to the present description,an immediate release dosage form that includes an opioid and thatincludes one or more abuse deterrent feature as described herein (e.g.,a gelling polymer, wax, solvent-resistant film, or a combinationthereof), can be formulated to not contain and to specifically excludean antagonist of an API that is also included in the dosage form, e.g.,an opioid antagonist in a dosage form containing an opioid.

Referring to FIGS. 1A and 1B, a dosage form can include particles 10Athat contain API. The particle (e.g., coated particle or “core-shell”particle) can include a core 12 a (or “uncoated core”), which may becoated with one or more layers, films or coatings, e.g., 14 a, 16 a, orany additional layer or coating that is coated over, underneath, orintermediate to these. In FIGS. 1B and 1C, the layer designated 16 a maybe an API containing layer, and the layer designated as 14 a may be asolvent resistant, e.g., a pH sensitive film layer. Particle 10A cancontain one or more of the ingredients described herein, such as any oneor more of API (especially an API that is susceptible to abuse), agelling polymer, optional wax, optional solvent-resistant layer, as wellas one or more additional layer or layers under, over, or intermediateto these layers or between either layer and the core. Each layer can bepresent in size or amount (e.g., thickness) that will result in a usefulimmediate release dosage form having one or more of the presentlydescribed abuse deterrent features. Other optional components of a coreor layer of particle 10 a can be filler, binder, other excipient, orsolvent (not more than a residual amount, if any) such as water orethanol for use in preparing the coated particle, and that issubstantially removed after formation of the core, coating, or coatedparticle. Examples of the core 10A can include any amount of thedifferent ingredients of: a gelling polymer (e.g. from 0 to 100 percentof a core), filler as described herein such as sugar (mannitol) ormicrocrystalline cellulose (e.g., from 0 to 100 percent of a core),binder (e.g., from 0 to 100 percent of a core), and wax (e.g., from 0 to100 percent of a core).

While core-shell particles 10 a are believed to be new and inventive,certain method steps useful to prepare these novel coated particles maybe known. Available methods include certain methods and processing stepsknown to be useful for preparing particles and coated particles in thepharmaceutical arts. A core-shell particle 10 a can be prepared by aninitial step of mixing ingredients of core 12 a with a solvent such aswater or ethanol and forming the mixture into a spherical core particleby known methods. The particle may be dried and separated by size, andthen one or more coating in the form of a continuous film or layer canbe applied to the core, optionally successively to produce multiplelayers surrounding the core. General processing to produce a multi-layercoated particle can include a series of steps such as compounding,mixing, granulation, wet milling, coating (by any method such asfluidized bed coating, spray coating, etc.), and one or more dryingsteps such as by use of a fluidized bed or other drying method.Intermittently between core-forming and coating steps, e.g., after adrying step, coated or uncoated particles can be sorted or separatedbased on size to produce a composition or a collection of particleshaving a desired size range and distribution. Accordingly, the coatedgranulate compositions according to the invention may be prepared by aprocess comprising:

-   -   (i) granulating a wax or a gelling polymer, or a mixture        thereof, in the presence of a hydroalcoholic solution or        suspension comprising a suitable binder, to form granules;    -   (ii) layering the granules formed in step (i) with a solution or        suspension comprising an API; and    -   (iii) coating the layered granules formed in step (ii) with a        solution or suspension comprising a film forming polymer        material to form a coated layered granulate.        The process above may further comprise steps of milling and        drying the granulate formed in step (i).

In instances wherein the core comprises a sugar sphere or amicrocrystalline cellulose sphere, the steps of the process above wouldbe modified as follows:

-   -   (i) providing a sugar sphere (or microcrystalline cellulose        sphere);    -   (ii) layering the sugar sphere (or microcrystalline cellulose        sphere) with a solution or suspension comprising an API; and    -   (iii) coating the layered sphere formed in step (ii) with a        solution or suspension comprising a film forming polymer        material to form a coated layered sphere.

Compressed tablets according to the invention may be prepared by aprocess comprising:

-   -   (i) combining the coated layered granulate (or the coated        layered sphere) prepared according to either of the above        processes with a second API (e.g., acetaminophen), a gelling        polymer, and a disintegrant, and optionally, with at least one        additional excipient selected from a filler, a colorant, and a        pH adjusting agent, to form a first mixture and then blending        the first mixture for a suitable time;    -   (ii) adding a lubricant to the blended mixture formed in        step (i) to form a second mixture, and then blending the second        mixture for a suitable time;    -   (iii) compressing the blended mixture formed in step (ii) to        form compressed tablets.

A suitable time for the blending in step (i) may be, for example, fromabout 5 to about 90 minutes, or from about 10 to about 60 minutes, orfrom about 20 to about 40 minutes, or about 30 minutes. A suitable timefor the blending in step (ii) may be, for example, from about 1 to about30 minutes, or from about 5 to about 20 minutes, or about 10 minutes.

In certain embodiments as shown at FIGS. 1A, 1B, and 1C, an immediaterelease dosage form as described can include a core-shell particle 10Athat includes a core 12A that contains only a minor amount of API orthat contains an insubstantial amount of API. Core 12A may contain lessthan 5 weight percent, e.g., less than 1 or less than 0.5 weight percentactive pharmaceutical ingredient based on a total weight of the core ofthe core-shell particle. Alternatively, core 12A may contain less than 5weight percent of a total amount of pharmaceutical ingredient in acore-shell polymer, e.g., less than 5, less than 1, or less than 0.5weight percent active pharmaceutical ingredient based on total weight ofAPI in the core-shell particle. In these embodiments a major portion ofAPI can be contained outside of core 12A, e.g., in an API layer 16 a,which can contain at least 50, at least 75, or at least 90, or at least95 weight percent of a total amount of the API in a core-shell polymer.

Core 12A can include binder, gelling polymer (e.g., HPMC), wax, orfiller, optionally alone or in combination, each in an amount to allowthe materials of the core to function as one or more abuse deterrentfeatures as described herein. See the examples included herewith forexamples of useful amounts and ranges of amounts of these ingredients.

Referring to FIG. 1A, core 12A contains gelling polymer, wax, binder, orfiller, or any combination of these, and no API (meaning not more thanan insignificant amount, such as less than 0.5 or less than 0.1 weightpercent based on the weight of core 12A). As shown at FIGS. 1B and 1C,core 12A, not containing API, can be coated with a coating layer thatcontains API, e.g., an active pharmaceutical layer or API layer 16A. Asshown at FIG. 1B, core-shell particle 10A includes core 12A, which doesnot contain any API, and API layer 16A, which contains an amount of API,such as a total amount of API (e.g., API commonly susceptible to abuse)to be contained in a dosage form prepared from particles 10A. API layer16A can contain one or more ingredients as described herein useful toform API layer 16A as a layer over an outer surface of core 12A. (API inAPI layer 16A can be a type of API that is commonly susceptible toabuse, such as an opioid, and can account for all of or most of (e.g.,at least 70, at least 80, at least 90, or at least 95 percent) the totalamount of that type of API in the core-shell particles and in the dosageform; in this embodiment the core can contain less than 10, less than 5,or less than 1 percent of the total amount of API in the core-shellparticles, and less than 10, 5, or 1 percent of the total amount of APIin the dosage form.) Useful non-API ingredients in an API layer caninclude a binder along with the API. The API and binder can be carriedin a solvent (e.g., water, ethanol, or both) and coated and dried toform a preferably continuous film layer on an outer surface of core 12A,i.e., API layer 16A. See the examples included herewith for examples ofuseful amounts and ranges of amounts of these ingredients.

A core-shell particle 10A can also optionally include a film layer,e.g., a solvent-resistant layer (e.g., a pH-sensitive layer) 14A asdescribed herein.

In certain alternate embodiments a dosage form as described can includea core-shell particle 10B that includes a core 12B that does contain auseful amount of API, such as an amount of API useful in an immediaterelease dosage form having one or more abuse deterrent features asdescribed herein, prepared to include particles 10B. See FIGS. 2A and2B. According to such embodiments, core 12B of particle 10B can containa gelling polymer, optional wax, optional binder or filler, and anamount of API.

Referring to FIG. 2A, core 12B contains gelling polymer, optional wax,optional binder, and API. Referring to FIG. 2B, core 12B, containingAPI, can optionally be coated with solvent-resistant layer (e.g., apH-sensitive layer) 14B as described herein for use in an immediaterelease dosage form. Core 12B may also optionally be coated with acoating layer that contains API, e.g., an active pharmaceutical layer orAPI layer prior to application of the solvent-resistant layer.Accordingly, API containing core-shell particles as described herein maycontain API of a type that is susceptible to abuse:

-   -   in an API layer surrounding the core and in a substantial amount        in the core;    -   in an API layer surrounding the core and in an insubstantial        amount in the core;    -   only in an API layer surrounding the core; or    -   only in the core.

In certain alternate embodiments, a dosage form as described can includea core-shell particle 10B, as depicted in FIG. 2B, that that does notcontain an API layer, and does not contain any API. Referring to FIG.2C, such a particle 10B, containing no API, may include core 12Bcontaining gelling polymer, optional wax, and optional binder, whichcore 12B may optionally be coated with solvent-resistant layer (e.g., apH-sensitive layer) 14B as described herein for use in an immediaterelease dosage form.

A coated particle 10 a or 10 b that includes API, and optionally, acoated particle 10B that does not include API, can be included in any ofa variety of dosage forms, examples including a compressed tablet orcompressed capsule, a suppository, capsule, caplet, pill, gel, softgelatin capsule, etc. As one example, a dosage form 12 can be preparedas a compressed tablet or compressed capsule. Tablet or capsule 12 cancontain core-shell particles 10 (e.g., 10A or 10B) distributed within amatrix 20, compressed to form the compressed tablet or capsule 12.Core-shell particles 10A or 10B can be as described herein, generally orspecifically, and can contain an amount of API suited to provide adesired dosage upon ingestion of tablet or capsule 12; e.g., matrix 20does not include any substantial amount of API.

Matrix 20 can include ingredients useful in combination with thecore-shell particles 10A, 10B, to produce an immediate release dosageform. Examples of useful excipients of an immediate release dosage formcan include ingredients that allow the dosage form to break up ordisintegrate upon ingestion and facilitate exposure to fluid in astomach, such as a useful amount of disintegrant. Examples of suchexcipients for such a dosage form can also include one or moreingredients that act as an abuse deterrent feature, such as a gellingpolymer as described herein. Other excipients can be useful forprocessing to form a compressed dosage form, and also may allow thecompressed dosage form to function as an immediate release dosage form,with one or more abuse deterrent features.

The following non-limiting examples show various dosage forms asdescribed herein. The described and exemplified dosage forms can be madefrom methods that include granulating, coating, and compressing steps asfollows.

General Procedure

Granulation

-   -   1. Glyceryl behenate and hypromellose K100M are dry mixed in a        high shear granulator. Hydroalcoholic solution of ethylcellulose        is added. Alternatively the granulation can be produced through        top spraying the hydroalcoholic solution in a fluid bed        granulator. Optionally, a portion of the ethyl cellulose, for        example from about 10 to about 50% by weight, or from about 10        to about 40% by weight, or from about 15 to about 30% by weight,        is dry mixed with the Glyceryl behenate and hypromellose K100M        prior to adding the hydroalcoholic solution containing the        balance of the ethyl cellulose.    -   1. (alternative when API is included in the core) Glyceryl        behenate and hypromellose K100M and API are dry mixed in a high        shear granulator. Hydroalcoholic solution of ethylcellulose is        added. Alternatively the granulation can be produced through top        spraying the hydroalcoholic solution in a fluid bed granulator.        Optionally, a portion of the ethyl cellulose, for example from        about 10 to about 50% by weight, or from about 10 to about 40%        by weight, or from about 15 to about 30% by weight, is dry mixed        with the Glyceryl behenate and hypromellose K100M prior to        adding the hydroalcoholic solution containing the balance of the        ethyl cellulose.    -   2. The granules are then wet milled using a size reduction mill        (Granumill) and then dried using a fluid bed, and optionally        screened.        Layering    -   3. The polymer granules are then layered using Wurster fluid bed        layering process with API (or alternatively, granulated using        high shear granulation or top spray fluid bed granulation        process).    -   3. (alternative when the coated granule will not contain API)        The layering step is omitted and the coating of Step 4 below is        applied to the granulate prepared in Step 1.        Coating    -   4. The layered granules of Step 3 (or alternatively, when the        coated granule will not contain API, the granules prepared in        Step 1) are then coated using a fluid bed coater equipped with a        Wurster insert (bottom spray assembly) with ethanolic suspension        of Eudragit E100 copolymer and magnesium stearate. Coated        particles are then screened and blended.        Blending and Tablet Compression

The blending, compression and bottling process for hydrocodone andacetaminophen tablets manufactured using the coated intermediate is asfollows:

-   -   1. The API-containing coated granules, APAP, crospovidone,        Carbopol 71G, sodium bicarbonate, mannitol, optionally, coated        granules containing no API, optionally, a glidant such as        colloidal silicon dioxide, and optionally a desired colorant,        are then added to the blender and mixed.    -   2. Magnesium stearate (and optionally colorant) is then added to        the blender and mixed. The blend is compressed into tablets        using a rotary tablet press.

Example 1: Preparation of Coated Granules

TABLE 1 Components for granule formulation Component % w/w hypromellose60 glyceryl behenate 26 ethyl cellulose 14 TOTAL 100

Granules were manufactured in a high shear granulator, wherehypromellose and glyceryl behenate were dry mixed for 3 minutes. Then, a10% hydroalcoholic solution of ethylcellulose N10 was slowly added whilemaintaining the granulator impeller and chopper speed at pre-selectedvalues that provide enough shear for granule formation and growth.Solution addition was continued until the entire amount ofethylcellulose was added. The granules were then wet milled using a sizereduction mill (Granumill) and were subsequently loaded into fluid bedfor drying.

TABLE 2 Components for layered granule formulation Component % w/whydrocodone bitartrate 10 polymer granules (EC, HPMC and Compritol) 85Hypromellose 2910 5 TOTAL 100

The prepared granules were then layered in a bottom spray fluid bedcoater with a 12% aqueous solution of hydrocodone bitartrate and HPMC2910.

TABLE 3 Components for coated granules formulation Component % w/wHydrocodone bitartrate layered granules, 10% 50 Eudragit E-100 33magnesium stearate 17 TOTAL 100

The hydrocodone bitartrate layered granules were then coated in a bottomspray fluid bed coater with 25% alcoholic suspension of Eudragit E-100copolymer and magnesium stearate. The resulting coated granules weresubsequently used for further blending and compression process.

Example 2: Hydrocodone/Acetaminophen Tablets

TABLE 4 Hydrocodone/acetaminophen Tablet Formulation Component %mg/tablet Hydrocodone bitartrate coated granules, 5% 20.0 200Paracetamol¹ 33.7 337 mannitol 10.3 103 carbopol 5.0 50 microcrystallinecellulose 12.0 120 crospovidone 15.0 150 sodium bicarbonate 3.0 30magnesium stearate 1.0 10 Total 100 1000 Contains 95% acetaminophen(APAP) and 5% gelatin

The coated granules were prepared according to Example 1 above and mixedwith paracetamol and other excipients (carbomer, crospovidone, sodiumbicarbonate, mannitol, microcrystalline cellulose) and blended in aV-blender for 30 minutes. Magnesium stearate was then added to lubricatethe blend and the mixture was blended for an additional 5 minutes priorto compressing into hydrocodone/acetaminophen tablets.

Example 3: Hydrocodone Bitartrate/Acetaminophen

TABLE 5 Hydrocodone/acetaminophen Granule Formulation Core Shellcomposition Component Location mg/tablet HPMC K100M Core 51.1 compritolCore 21.9 Ethocel Core 12 hydrocodone bitartrate API layer 10 HPMC 2910API layer 5 Eudragit E-100 Film 66.7 magnesium stearate Film 33.3 Total200

TABLE 6 Hydrocodone/acetaminophen Tablet Formulation Componentsmg/tablet Core Shell composition (above) 200 APAP 325 gelatin 12.1mannitol 42.9 carbopol 50 microcrystalline cellulose 130 crospovidone200 sodium bicarbonate 30 magnesium stearate 10 Total 1000

TABLE 7 Hydrocodone/acetaminophen Overall Tablet composition OverallTablet composition Components mg/tablet HPMC K100M 51.1 compritol 21.9Ethocel 12 hydrocodone bitartrate 10 HPMC 2910 5 Eudragit E-100 66.7APAP* 325 gelatin 12.1 mannitol 42.9 carbopol 50 microcrystallinecellulose 130 crospovidone 200 sodium bicarbonate 30 magnesium stearate43.3 Total 1000 *acetaminophen (acetyl-para-aminophenol).

Coated granules were prepared according to the procedure described inExample 1. The prepared coated granules were then mixed withacetaminophen and other excipients (carbopol, crospovidone, sodiumbicarbonate, mannitol, microcrystalline cellulose) and blended in aV-blender for 30 minutes. Magnesium stearate was then added to lubricatethe blend and the mixture was blended for an additional 5 minutes priorto compressing into hydrocodone/acetaminophen tablets.

Example 4: Hydrocodone Bitartrate/Acetaminophen

TABLE 8 Hydrocodone/acetaminophen granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 25.5 compritolcore 10.9 Ethocel core 6 hydrocodone bitartrate API layer 5 HPMC 2910API layer 2.5 Eudragit E-100 film 33.4 magnesium stearate film 16.7Total 100

TABLE 9 Hydrocodone/acetaminophen tablets Component mg/Tab Core Shellcomposition (above) 100 APAP 325 gelatin 12.14 mannitol 34.88 carbopol50 microcrystalline cellulose 96 crospovidone 144 sodium bicarbonate 30magnesium stearate 8 Total 800.02

Coated granules were prepared according to the procedure described inExample 1. The prepared coated granules were then mixed withacetaminophen and other excipients (carbopol, crospovidone, sodiumbicarbonate, mannitol, microcrystalline cellulose) and blended in aV-blender for 30 minutes. Magnesium stearate was then added to lubricatethe blend and the mixture was blended for an additional 5 minutes priorto compressing into hydrocodone/acetaminophen tablets.

TABLE 10 Hydrocodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 25.5 compritol 10.9 ethocel6 hydrocodone bitartrate 5 HPMC 2910 2.5 Eudragit E-100 33.4 APAP 325gelatin 12.14 mannitol 34.88 carbopol 50 microcrystalline cellulose 96crospovidone 144 sodium bicarbonate 30 magnesium stearate 24.7 Total800.02

Example 5: Hydrocodone Bitartrate/Acetaminophen

TABLE 11 Hydrocodone/acetaminophen granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 50.1 compritolcore 21.5 ethocel core 11.8 hydrocodone bitartrate API layer 9.8 HPMC2910 API layer 4.9 Eudragit E-100 film 65.4 magnesium stearate film 32.7Total 196.2

TABLE 12 Hydrocodone/acetaminophen tablet composition Component mg/TABCore Shell composition (above) 196.1 APAP 325 gelatin 12.14 mannitol46.2 carbopol 50 microcrystalline cellulose 130 crospovidone 200 rediron oxide 0.6 sodium bicarbonate 30 magnesium stearate 10 Total 1000

Coated granules were prepared according to the procedure described inExample 1. The prepared coated granules were then mixed withacetaminophen and other excipients (carbopol, crospovidone, sodiumbicarbonate, mannitol, red iron oxide, microcrystalline cellulose) andblended in a V-blender for 30 minutes. Magnesium stearate was then addedto lubricate the blend and the mixture was blended for an additional 5minutes prior to compressing into hydrocodone/acetaminophen tablets.

TABLE 13 Hydrocodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 50.1 compritol 21.5 ethocel11.8 hydrocodone bitartrate 9.8 HPMC 2910 4.9 Eudragit E-100 65.4 APAP325 gelatin 12.14 mannitol 46.2 carbopol 50 microcrystalline cellulose130 crospovidone 200 red iron oxide 0.6 sodium bicarbonate 30 magnesiumstearate 42.7 Total 1000.14

Example 6: Oxycodone Hydrochloride (Single API) (Celphere Core)

TABLE 14 Oxycodone granule composition Core Shell composition ComponentsLocation mg/tablets Celphere (MCC) core 42 oxycodone hydrochloride APIlayer 5.2 HPMC 2910 API layer 1.7 Eudragit E-100 film 1.9 magnesiumstearate film 0.6 Total 51.4

Microcrystalline cellulose particles were layered in a bottom sprayfluid bed coater with a 12% aqueous solution of oxycodone hydrochlorideand HPMC 2910.

The oxycodone hydrochloride layered particles were then coated in abottom spray fluid bed coater with 25% alcoholic suspension of EudragitE-100 copolymer and magnesium stearate. The resulting coated particleswere subsequently used for further blending and compression process.

TABLE 15 Oxycodone tablet composition Component mg/TAB Core Shellcomposition (above) 51.54 lactose 96.46 microcrystalline cellulose 40crospovidone 10 magnesium stearate 2 Total 200

The coated particles were mixed with other excipients (crospovidone andlactose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into oxycodone tablets.

TABLE 16 Oxycodone hydrochloride tablet composition Overall Tabletcomposition Components mg/tablet microcrystalline cellulose 82 oxycodonehydrochloride 5.2 HPMC 2910 1.7 Eudragit E-100 1.9 lactose 96.46crospovidone 10 magnesium stearate 2.6 Total 199.86

Example 7: Hydrocodone Bitartrate/Acetaminophen (Sugar Sphere Core)

TABLE 17 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet sugar sphere core 47.3 PEO core24.7 EPO core 20.5 hydrocodone bitartrate API layer 5 HPMC 2910 APIlayer 2.5 Eudragit E-100 film 75 magnesium stearate film 25 Total 200

Sugar sphere particles were layered in a bottom spray fluid bed coaterwith an aqueous solution of hydrocodone bitartrate and HPMC 2910.

The hydrocodone bitartrate layered particles were then coated in abottom spray fluid bed coater with 25% alcoholic suspension of EudragitE-100 copolymer and magnesium stearate. The resulting coated particleswere subsequently used for further blending and compression process.

TABLE 18 Hydrocodone bitartrate tablet composition mg/tablet Core Shellcomposition (above) 200 APAP 325 binder 17.8 mannitol 192.2microcrystalline cellulose 200 crospovidone 50 magnesium stearate 15Total 1000

The coated spheres were mixed with acetaminophen and other excipients(mannitol, microcrystalline cellulose, binder and crospovidone) andblended in a V-blender for 30 minutes. Magnesium stearate was then addedto lubricate the blend and the mixture was blended for an additional 5minutes prior to compressing into oxycodone tablets.

TABLE 19 Hydrocodone bitartrate tablet composition Overall Tabletcomposition Components mg/tablet sugar 47.3 PEO(polyethylene oxide) 24.7EPO(Eudragit E-PO) 20.5 hydrocodone bitartrate 5 HPMC 2910 2.5 EudragitE-100 75 APAP 325 binder 17.8 mannitol 192.2 microcrystalline cellulose200 crospovidone 50 magnesium stearate 40 Total 1000

Example 8: Hydrocodone Bitartrate/Acetaminophen (Celphere Core)

TABLE 20 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet Celphere (MCC) core 117.5hydrocodone bitartrate API layer 5 HPMC 2910 API layer 2.5 EudragitE-100 film 83.4 magnesium stearate film 41.6 Total 250

TABLE 21 Hydrocodone bitartrate tablet composition Component mg/tabletCore Shell composition (above) 250 APAP 325 gelatin 12.14 mannitol 102.9microcrystalline cellulose 120 xanthan gum 30 crospovidone 150 magnesiumstearate 10 Total 1000.04

Coated spheres were prepared as in Example 7, and mixed withacetaminophen and other excipients (mannitol, microcrystallinecellulose, xanthan gum and crospovidone) and blended in a V-blender for30 minutes. Magnesium stearate was then added to lubricate the blend andthe mixture was blended for an additional 5 minutes prior to compressinginto hydrocodone tablets.

TABLE 22 Hydrocodone bitartrate granule composition Overall Tabletcomposition Component mg/tablet microcrystalline cellulose 237.5hydrocodone bitartrate 5 HPMC 2910 2.5 Eudragit E-100 83.4 APAP 325gelatin 12.14 mannitol 102.9 xanthan gum 30 crospovidone 150 magnesiumstearate 51.6 Total 1000.04

Example 9: Hydrocodone Bitartrate/Acetaminophen (Celphere Core)

TABLE 23 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet Celphere (MCC) core 117.5hydrocodone bitartrate API layer 5 HPMC 2910 API layer 2.5 EudragitE-100 film 83.4 magnesium stearate film 41.6 Total 250

TABLE 24 Hydrocodone bitartrate tablet composition Component mg/tabletCore Shell composition (above) 250 APAP 325 gelatin 12.14 mannitol 84.9microcrystalline cellulose 120 Carbopol 30 sodium bicarbonate 18crospovidone 150 magnesium stearate 10 Total 1000.04

Coated spheres were prepared as in Example 7, and mixed withacetaminophen and other excipients (mannitol, microcrystallinecellulose, carbopol, sodium bicarbonate and crospovidone) and blended ina V-blender for 30 minutes. Magnesium stearate was then added tolubricate the blend and the mixture was blended for an additional 5minutes prior to compressing into tablets.

TABLE 25 Hydrocodone bitartrate tablet composition Overall Tabletcomposition Components mg/tablet hydrocodone bitartrate 5 HPMC 2910 2.5Eudragit E-100 83.4 APAP 325 gelatin 12.14 mannitol 84.9microcrystalline cellulose 237.5 carbopol 30 sodium bicarbonate 18crospovidone 150 magnesium stearate 51.6 Total 1000.04

Example 10: Oxycodone Hydrochloride/Acetaminophen

TABLE 26 Oxycodone bitartrate granule composition Core Shell compositionComponent Location mg/tablet HPMC K100M core 71 Compritol core 30.5Ethocel core 16.8 oxycodone hydrochloride API layer 4.5 HPMC 2910 APIlayer 2.2 Eudragit E-100 film 83.4 magnesium stearate film 41.6 Total250

TABLE 27 Oxycodone tablet composition Component mg/tablet Core Shellcomposition (above) 250 APAP 325 gelatin 12.14 lactose 84.9 carbopol 30microcrystalline cellulose 120 crospovidone 150 sodium bicarbonate 18magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into oxycodone/acetaminophentablets.

TABLE 28 Oxycodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 71 compritol 30.5 ethocel16.8 oxycodone hydrochloride 4.5 HPMC 2910 2.2 Eudragit E-100 83.4 APAP325 gelatin 12.14 lactose 84.9 carbopol 30 microcrystalline cellulose120 crospovidone 150 sodium bicarbonate 18 magnesium stearate 51.6 Total1000

Example 11: Oxycodone Hydrochloride/Acetaminophen

TABLE 29 Oxycodone hydrochloride granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 71 compritolcore 30.3 ethocel core 16.7 oxycodone hydrochloride API layer 5 HPMC2910 API layer 2.5 Eudragit E-100 film 83.4 magnesium stearate film 41.6Total 250.5

TABLE 30 Oxycodone/acetaminophen tablet composition Component mg/tabletCore Shell composition (above) 250 APAP 325 gelatin 12.14 mannitol 82.9xanthan gum 50 microcrystalline cellulose 120 crospovidone 150 magnesiumstearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(xanthan gum, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose) and blended in a V-blender for 30 minutes.Magnesium stearate was then added to lubricate the blend and the mixturewas blended for an additional 5 minutes prior to compressing intooxycodone/acetaminophen tablets.

TABLE 31 Oxycodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 71 Compritol 30.3 Ethocel16.7 oxycodone hydrochloride 5 HPMC 2910 2.5 Eudragit E-100 83.4 APAP325 gelatin 12.14 mannitol 82.9 xanthan gum 50 microcrystallinecellulose 120 crospovidone 150 magnesium stearate 51.6 Total 1000.54

Example 12: Oxycodone Hydrochloride/Acetaminophen

TABLE 32 Oxycodone hydrochloride granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 71 Compritolcore 30.5 Ethocel core 16.8 oxycodone hydrochloride API layer 4.5 HPMC2910 API layer 2.2 Eudragit E-100 film 83.4 magnesium stearate film 41.6Total 250

TABLE 33 Oxycodone/acetaminophen tablet composition Component mg/tabletCore Shell composition (above) 250 APAP 325 gelatin 12.14 mannitol 52.9Carbopol 50 microcrystalline cellulose 120 Crospovidone 150 sodiumbicarbonate 30 magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into oxycodone/acetaminophentablets.

TABLE 34 Oxycodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 71 compritol 30.5 ethocel16.8 oxycodone hydrochloride 4.5 HPMC 2910 2.2 Eudragit E-100 83.4 APAP325 gelatin 12.14 mannitol 52.9 carbopol 50 microcrystalline cellulose120 crospovidone 150 sodium bicarbonate 30 magnesium stearate 51.6 Total1000

Example 13: Hydrocodone Bitartrate/Acetaminophen

TABLE 35 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 51 compritolcore 21.9 ethocel core 12 hydrocodone bitartrate API layer 10 HPMC 2910API layer 5 Eudragit E-100 film 66.7 magnesium stearate film 33.3 Total199.9

TABLE 36 Hydrocodone Bitartrate/APAP tablet composition Component mg/TABCore Shell composition (above) 200 APAP 325 gelatin 12.14 mannitol 74.86carbopol 80 microcrystalline cellulose 100 crospovidone 150 sodiumbicarbonate 48 magnesium stearate 10 Total 1000

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into hydrocodone/acetaminophentablets.

TABLE 37 Hydrocodone Bitartrate/APAP tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 51 Compritol 21.9 Ethocel 12hydrocodone bitartrate 10 HPMC 2910 5 Eudragit E-100 66.7 APAP 325gelatin 12.14 mannitol 74.86 carbopol 80 microcrystalline cellulose 100crospovidone 150 sodium bicarbonate 48 magnesium stearate 43.3 Total999.9

Example 14: Hydrocodone Bitartrate/Acetaminophen

TABLE 38 Hydrocodone Bitartrate granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 42 compritolcore 18.1 ethocel core 9.9 hydrocodone bitartrate API layer 10 HPMC 2910API layer 5 Eudragit E-100 film 56.8 magnesium stearate film 28.4 Total170.2

TABLE 39 Hydrocodone/APAP tablet composition Component mg/tablet CoreShell composition (above) 170 APAP 325 gelatin 12.14 mannitol 24.905carbopol 49.98 microcrystalline cellulose 102 crospovidone 127.5 sodiumbicarbonate 30.005 magnesium stearate 8.5 Total 850.03

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into hydrocodone/acetaminophentablets.

TABLE 40 Hydrocodone/APAP tablet composition Overall Tablet compositionComponents mg/tablet HPMC K100M 42 compritol 18.1 ethocel 9.9hydrocodone bitartrate 10 HPMC 2910 5 Eudragit E-100 56.8 APAP 325gelatin 12.14 mannitol 24.905 carbopol 49.98 microcrystalline cellulose102 crospovidone 127.5 sodium bicarbonate 30.005 magnesium stearate 36.9Total 850.23

Example 15: Hydrocodone Bitartrate/Acetaminophen

TABLE 41 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 51 compritolcore 21.9 ethocel core 12 hydrocodone bitartrate API layer 10 HPMC 2910API layer 5 Eudragit E-100 film 66.7 magnesium stearate film 33.3 Total199.9

TABLE 42 Hydrocodone/APAP tablet composition Component mg/tablet CoreShell composition (above) 200 APAP 325 gelatin 12.14 mannitol 134.9carbopol 30 microcrystalline cellulose 120 crospovidone 150 sodiumbicarbonate 18 magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into hydrocodone/acetaminophentablets.

TABLE 43 Hydrocodone/APAP tablet composition Overall Tablet compositionComponent mg/tablet HPMC K100M 51 compritol 21.9 ethocel 12 hydrocodonebitartrate 10 HPMC 2910 5 Eudragit E-100 66.7 APAP 325 gelatin 12.14mannitol 134.9 carbopol 30 microcrystalline cellulose 120 crospovidone150 sodium bicarbonate 18 magnesium stearate 43.3 Total 999.94

Example 16: Hydrocodone Bitartrate/Acetaminophen

TABLE 44 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 51 compritolcore 21.9 ethocel core 12 hydrocodone bitartrate API layer 10 HPMC 2910API layer 5 Eudragit E-100 film 66.7 magnesium stearate film 33.3 Total199.9

TABLE 45 Hydrocodone/APAP tablet composition Component mg/tablet CoreShell composition (above) 200 APAP 325 gelatin 12.14 mannitol 102.9carbopol 50 microcrystalline cellulose 120 Crospovidone 150 sodiumbicarbonate 30 magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into hydrocodone/acetaminophentablets.

TABLE 46 Hydrocodone/APAP tablet composition Overall Tablet compositionComponents mg/tablet HPMC K100M 51 Compritol 21.9 Ethocel 12 hydrocodonebitartrate 10 HPMC 2910 5 Eudragit E-100 66.7 APAP 325 gelatin 12.14mannitol 102.9 carbopol 50 microcrystalline cellulose 120 crospovidone150 sodium bicarbonate 30 magnesium stearate 43.3 Total 999.94

Example 17: Hydrocodone Bitartrate/Acetaminophen

TABLE 47 Hydrocodone/APAP tablet composition Components (mg/tab) 5/325mg 7.5/325 mg 10/325 mg Hypromellose K100M PH 25.5 38.3 51.1 Compritol888 ATO 11 16.4 21.9 ethyl cellulose 6 9 12 hydrocodone bitartrate 5 7.510 Hypromellose 2910 2.5 3.8 5 Eudragit E-100 33.4 50 66.7 paracetamolDc272n** 342.11 342.11 342.11 mannitol Ez 29.89 38.81 37.29 carbopol 71g50 50 50 microcrystalline cellulose 96 108 130 crospovidone 144 171 200sodium bicarbonate #1 30 30 30 FD&C Blue #2 Ht Aluminum Lake NA 0.54 NAIron Oxide Yellow 510p NA 0.54 NA Iron Oxide Red 212p NA NA 0.6magnesium stearate non-bovine 24.6 34 43.3 alcohol SDA-3A,anhydrous* * * * purified water* * * * Total Tablet Weight 800 900 1000*Removed during Processing **Contains 95% acetaminophen (APAP) and 5%binder.

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with Paracetamol and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose and coloring agents) and blended in a V-blender for 30minutes. Magnesium stearate was then added to lubricate the blend andthe mixture was blended for an additional 5 minutes prior to compressinginto hydrocodone/acetaminophen tablets.

TABLE 48 Hydrocodone bitartrate granule composition 5/325 mg 7.5/325 mg10/325 mg Dose Dose Dose % % % Granulation Hypromellose 3.19 4.26 5.11Compritol 888 ATO 1.37 1.83 2.19 ethylcellulose 0.75 1 1.2 alcoholSDA-3A, anhydrous * * * purified water * * * TOTAL 5.31 7.09 8.5Layering hydrocodone bitartrate 0.63 0.83 1 polymer granules (EC, HPMCand 5.31 7.09 8.5 Compritol) Hypromellose 2910 0.31 0.42 0.5 purifiedwater * * * TOTAL 6.25 8.34 10 Coating hydrocodone layered granules,6.25 8.34 10 10% Eudragit E-100 4.17 5.56 6.67 magnesium stearate 2.082.77 3.33 alcohol, SDA-3A, anhydrous * * * TOTAL 12.5 16.67 20 * Removedduring Processing

Example 18: Armodafinil

TABLE 49 Armodafinil tablet composition Armodafinil: Components (mg/tab)50 mg 150 mg 200 mg hypromellose 64.26 36 48 Compritol 888 ATO 17.85 1014 ethylcellulose 10.71 10 14 armodafinil 50 150 200 Eudragit E-100 2130 40 Mannitol Ez 17 25 25 Carbopol 71g 50 50 50 microcrystallinecellulose 100 125 125 crospovidone 150 200 200 sodium bicarbonate #1 3030 30 magnesium stearate non-bovine 71 25 32 Lutrol F68 (1:5) 150 200200 sodium lauryl sulphate (3%) 23 30 40 Alcohol SDA-3A,anhydrous* * * * purified water* * * * Total Tablet Weight 754.82 9211018 *Removed during Processing

Granules are prepared and coated as described in Example 1. The coatedgranules are then mixed with the other excipients (carbopol,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate(non-bovine) is then added to lubricate the blend and the mixture isblended for an additional 5 minutes prior to compressing intoarmodafinil tablets.

TABLE 50 Armodafinil granule compositions 50 mg Dose 150 mg Dose 200 mgDose mg/g mg/tab mg/g mg/tab mg/g mg/tab Granulation hypromellose 45064.26 175 36 175 48 armodafinil 350 49.98 725 150 725 200 Compritol 888ATO 125 17.85 50 10 50 14 ethylcellulose 75 10.71 50 10 50 14 AlcoholSDA-3A, * * * * * * anhydrous purified water * * * * * * TOTAL 1000142.8 1000 206 1000 276 Coating armodafinil granules, 820 142.84 820 207820 276 35% Eudragit E-100 120 20.90 120 30 120 40 magnesium stearate 6010.45 60 15 60 20 Alcohol, SDA-3A, * * * * * * anhydrous TOTAL 1000174.2 1000 252 1000 336 * Removed during Processing

Example 19: Phenobarbital

TABLE 51 Phenobarbital Tablet compositions Components (mg/tab) 15 mg 30mg 60 mg 100 mg hypromellose 19.3 38.6 77.2 128.52 Compritol 888 ATO 5.410.7 21.4 35.7 ethylcellulose 3.2 6.4 12.9 21.43 phenobarbital 15 30 60100 Eudragit E-100 6.3 15.5 25.1 42 Mannitol EZ 20 20 20 20.1 Carbopol71g 50 50 50 50 microcrystalline cellulose 100 100 100 100 crospovidone130 130 130 200 sodium bicarbonate #1 30 30 30 30 magnesium stearatenon-bovine 9.1 12.3 19.1 31 Lutrol F68 (1:5) 100 100 120 200 sodiumlauryl sulphate (3%) 22.8 28 35 50 Alcohol SDA-3A, anhydrous* * * * *purified water* * * * * Total Tablet Weight 511.1 571.5 700.7 1008.7*Removed during Processing

TABLE 52 Phenobarbital granule compositions 15 mg Dose 30 mg Dose 60 mgDose 100 mg Dose mg/g mg/tab mg/g mg/tab mg/g mg/tab mg/g mg/tabGranulation Hypromellose 450 19.31 450 38.57 450 77.18 450 128.57phenobarbital 350 15.02 350 30 350 60.03 350 100 Compritol 888 ATO 1255.36 125 10.71 125 21.44 125 35.71 ethyl cellulose 75 3.22 75 6.43 7512.86 75 21.43 Alcohol SDA-3A, * * * * * * * * PurifiedWater * * * * * * * * TOTAL 1000 42.91 1000 85.71 1000 171.51 1000285.71 Coating phenobarbital, 35% 820 42.89 820 85.69 820 171.46 820285.69 Eudragit E-100 120 6.28 120 12.54 120 25.09 120 41.81 magnesiumstearate 60 3.14 60 6.27 60 12.55 60 20.90 Alcohol,SDA-3A, * * * * * * * * TOTAL 1000 52.3 1000 104.5 1000 209.1 1000348.4 * Removed during Processing

Granules are prepared and coated as described in Example 1. The coatedgranules are then mixed with the other excipients (carbopol,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate(non-bovine) is then added to lubricate the blend and the mixture isblended for an additional 5 minutes prior to compressing intophenobarbital tablets.

Example 20: Diazepam

TABLE 53 Diazepam Tablet compositions 2 mg 5 mg 10 mg Components(mg/tab) (mg/tab) (mg/tab) Hypromellose K100M PH 22.2 55.6 111.2Compritol 888 ATO 9.5 23.8 47.64 Ethyl cellulose N10 5.2 13.1 26.2diazepam 2 5 10 Hypromellose 2910 1 2.5 5 Eudragit E-100 26.7 66.7 133.4mannitol Ez 70 70 70 carbopol 71g 50 50 50 microcrystalline cellulose 9595 94 crospovidone 90 95 150 sodium bicarbonate #1 30 30 30 magnesiumstearate non- 18.1 38.6 74.6 Alcohol SDA-3A, * * * purified water* * * *Total Tablet Weight 419.7 545.3 802.04 *Removed during processing

Granules are prepared and coated as described in Example 1. The coatedgranules are then mixed with the other excipients (carbopol,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate(non-bovine) is then added to lubricate the blend and the mixture isblended for an additional 5 minutes prior to compressing into Diazepamtablets.

TABLE 54 Diazepam Coated Granule compositions 2 mg Dose 5 mg Dose 2 mgDose mg/g mg/tab mg/g mg/tab mg/g mg/tab Granulation hypromellose 600.8622.23 600.86 55.58 600.86 111.16 Compritol 888 257.51 9.53 257.51 23.82257.51 47.64 ATO ethyl cellulose 141.63 5.24 141.63 13.10 141.63 26.20Alcohol * * * * * * SDA-3A, purified water * * * * * * TOTAL 1000 371000 92.5 1000 185 Layering diazepam 50 2 50 5 50 10 polymer 925 37 92592.5 925 185 granules (EC, Hypromellose 25 1 25 2.5 25 5 2910 purifiedwater * * * * * * TOTAL 1000 40 1000 100 1000 200 Coated, 2.5% diazepam500 40 500 100 500 200 layered Eudragit E-100 333.6 26.69 333.6 66.71333.6 133.43 magnesium 166.4 13.31 166.4 33.29 166.4 66.57 stearateAlcohol, * * * * * * SDA-3A, TOTAL 1000 80 1000 200 1000 400

Example 21: Hydrocodone (Single API)

Granules are prepared and coated as described in Example 1. The coatedgranules are then mixed with the other excipients (carbopol,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate(non-bovine) is then added to lubricate the blend and the mixture isblended for an additional 5 minutes prior to compressing intohydrocodone tablets.

Example 22: Hydrocodone (Single API)—(Continued from Example 21 Above)

TABLE 55 Hydrocodone Tablet compositions Components 5 mg (mg/tab) 10 mg(mg/tab) Hypromellose K100M PH 25.5 51.1 Compritol 888 ATO 11 21.9 Ethylcellulose N10 6 12.04 hydrocodone bitartrate 5 10 Hypromellose 2910 2.55 Eudragit E-100 33.4 66.7 Mannitol Ez 70 70 Carbopol 71G 50 50microcrystalline cellulose 95 95 Crospovidone 100 120 Sodium Bicarbonate#1 30 30 Magnesium Stearate Non-Bovine 21.6 39.3 Alcohol SDA-3A,Anhydrous* * * purified water* * * Total Tablet Weight 450 571.04*Removed during processing

TABLE 56 Hydrocodone bitartrate Coated Granule compositions 5 mg Dose 10mg Dose mg/g mg/tab mg/g mg/tab Granulation Hypromellose 600.86 25.54600.86 51.07 Compritol 888 ATO 257.51 10.94 257.51 21.89 ethyl cellulose141.63 6.02 141.63 12.04 Alcohol SDA-3A, anhydrous * * * * purifiedwater * * * * TOTAL 1000 42.5 1000 85 Layering hydrocodone bitartrate100 5 100 10 polymer granules (EC, HPMC 850 42.5 850 85 and Compritol)Hypromellose 2910 50 2.5 50 5 purified water * * * * TOTAL 1000 50 1000100 Coating hydrocodone bitartrate layered 500 50 500 100 granules, 10%Eudragit E-100 333.6 33.36 333.6 66.71 magnesium stearate 166.4 16.64166.4 33.29 Alcohol, SDA-3A, anhydrous * * * * TOTAL* (removed during1000 100 1000 200 processing)

Example 23: Hydrocodone Bitartrate/Acetaminophen

Coated granules were prepared according to the Example 1 above. Theprepared coated granules were then mixed with Paracetamol and otherexcipients (carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose, colorants such as FD and C blue, red ironoxide or yellow iron oxide are premixed and blended in a bin blender for30 minutes. Magnesium stearate was then added to lubricate the blend andthe resulting mixture was blended for an additional 5 minutes prior tocompressing into hydrocodone/acetaminophen tablets.

TABLE 57 Hydrocodone/APAP Tablet compositions Component (% w/w) 5/325 mg7.5/325 mg 10/325 mg Hydrocodone bitartrate coated 12.5 16.7 20.0Paracetamol* 42.76 38.0 34.21 Mannitol 3.74 4.3 3.73 carbopol 6.25 5.65.0 microcrystalline cellulose 12.0 12.0 13.0 Crospovidone 18.0 19.020.0 sodium bicarbonate 3.75 3.3 3.0 FD&C Blue #2 HT Aluminum NA 0.06 NALake Iron Oxide Red 212P NA NA 0.06 Iron Oxide Yellow 510P NA 0.06 NAmagnesium stearate 1.0 1.0 1.0 Total 100 100 100 *Contains 95%acetaminophen (APAP) and 5% binder

Example 24: Extraction Study of Formulations According to Examples 3

The dosage form (intact and crushed) prepared according to Example 3above (10/325 mg hydrocodone bitartrate/Acetaminophen tablet) was takenup in a small volume of water and extracted to simulate the amount ofhydrocodone that was available to abusers via intravenous (IV) route.The resultant mixture was assessed for ability to draw the mixturethrough a filter material into a syringe for IV injection. Variousneedle sizes and extraction volumes were evaluated. Filtrates wereassayed by HPLC for content of hydrocodone bitartrate.

TABLE 58 Amount of hydrocodone extracted from two lots of 10/325 mghydrocodone bitartrate/Acetaminophen tablets at 100° C. and RoomTemperature (RT) Intact tablet (mg) Crushed tablet (mg) Lot # 100° C. RT100° C. RT 1 0 mg 0.09 mg 0 mg 0 mg 2 0 mg 0.07 mg 0 mg 0 mg

Example 25: Simulated Nasal Fluid Extraction Study of FormulationsAccording to Example 3

The dosage form prepared according to Example 3 above (10/325 mghydrocodone bitartrate/Acetaminophen tablets) was crushed using a pestleand mortar and placed in 10 mL of simulated nasal fluid at 37° C., withgentle agitation to simulate the amount of hydrocodone bitartrateavailable for abuse by nasal insufflation. Aliquots were removed at 10and 30 minutes for analysis of hydrocodone bitartrate by HPLC. Theamount of hydrocodone bitartrate extracted from crushed tablets forsimulated nasal insufflation is provided in the table below.

This method is for the determination of hydrocodone bitartrate releasedfrom simulated nasal fluid extractions of hydrocodone bitartrateextended-release tablets.

A. HPLC Analysis Parameters

Column GL Sciences Inertsil Phenyl-3, 4.6 mm × 50 mm, 5-μm ColumnTemperature 45° C. Detection UV at 280 nm Solvent A 0.1% HFBA in waterSolvent B MeOH Mobile Phase 70:30 Solvent A:Solvent B Injector Flush50:50 MeOH:water Flow Rate 2.0 mL/min Injection Volume 50 μL Run Time 4min Peak Response Area Diluent 0.1N HCl

B. HPLC Solution Preparation

Solvent A (0.1% HFBA in H₂O): Combine 1 mL of HFBA and 1 L of HPLC gradewater, and mix well. Solvent A is stable for 14 days. Proportionatevolumes may be prepared. Mobile Phase (70:30 Solvent A:MeOH): Combine700 mL of Solvent A and 300 mL of MeOH, and mix well. Prepared solutionsare stable for 1 month. Proportionate volumes may be prepared.Alternatively, the HPLC pump may be used to mix the mobile phase.Diluent/Medium (0.1 N HCl): Combine 25 mL of 12 N HCl and 3 L of DIwater, and mix well. 0.1N HCl is stable for 4 weeks. Proportionatevolumes may be prepared. Injector Flush (50:50 MeOH:H₂O): Combine 500 mLof MeOH and 500 mL of HPLC grade water, and mix well. 50:50 MeOH:H₂O isstable for 1 month. Proportionate volumes may be prepared.

C. Simulated Nasal Fluid (SNF) Preparation

Add 8.7 g sodium chloride (NaCl) 3.0 g potassium chloride (KCl), 0.6 gcalcium chloride (CaCl₂), 4.4 g sodium phosphate dibasic (Na₂HPO₄), and1.1 g sodium phosphate monobasic (NaH2PO4) in one liter of water. Mixwell. Measure and record pH (must be between 6.0 and 7.0). Store at roomtemperature. SNF is stable for 2 weeks. Proportionate volumes may beprepared.

D. Hydrocodone Bitartrate Standard Solution

Stock Standard Solution: Dry a portion of hydrocodone bitartratestandard at 2 hours under vacuum at 105° C. per the USP. In duplicate,accurately weigh 30 mg±5 mg of hydrocodone bitartrate into separate100-mL volumetric flasks. Add approximately 50 mL of 0.1 N HCl diluent.Dissolve by sonication for approximately 10 minutes. Dilute to volumewith diluent, and mix well. These are the stock standard solutions ofapproximately 300 micrograms/mL (as anhydrous hydrocodone bitartrate)and are stable for 29 days under ambient laboratory conditions(unprotected from light). Proportionate volumes may be prepared.

Working Standard Solution: Pipette 15 mL of each stock standard solutioninto separate 50-mL volumetric flasks. Dilute to volume with 0.1 N HCldiluent, and mix well. These working standard solutions areapproximately 90 micrograms/mL (as anhydrous hydrocodone bitartrate) andare stable for 43 days under ambient laboratory conditions (unprotectedfrom light). Proportionate volumes may be prepared.

E. Simulated Nasal Insufflation Extraction Sample Preparation

1. Crush one tablet and transfer approximately 575 mg, accuratelyweighed, of the crushed material to pre-labeled 20 mL glass vial. Fordrug substance controls, weigh an appropriate mass of material andtransfer into a pre-labeled 20 mL glass vial.

2. Heat the water bath and simulated nasal fluid to 37° C.

3. Pipette 10 mL the pre-heated 37° C. simulated nasal fluid into eachvial containing crushed tablet material.

4. Cap and invert two times to wet powder. Put vial on the metal shelfinside of the water bath and shake at 100 rpm.

5. At 10 min, take the vial out of shelf.

6. Uncap and withdraw a 3-mL solution from each of the vials using amicropipette.

7. Transfer solution into a 5-mL polypropylene syringe and filter thesolution through a 25-mm diameter, 1-μm porosity glass filter into aglass test tube (16×100 mm).

8. Place vial back into water bath and continue shaking.

9. At 30 min, stop the shaking, uncap and withdraw a 3-mL solution fromeach of the vials using a micropipette.

10. Transfer solution into a 5-mL polypropylene syringe and filter thesolution through a 25-mm diameter, 1-μm porosity glass filter into aglass test tube (16×100 mm).

11. Pipette 1 mL of solution from each test tube into separate 50-mLvolumetric flasks and dilute to volume with 0.1 N HCl. Mix by inverting10 times.

12. Pass and discard a 1-mL aliquot of the sample solution through a25-mm diameter, 1-μm porosity, glass syringe filter prior to collectionof a second aliquot into a glass HPLC vial and cap.

13. Inject each sample once.

TABLE 59 Simulated nasal fluid extraction of 10/325 mg hydrocodonebitartrate/Acetaminophen tablets Amount extracted at 10 minutes Amountextracted at 30 minutes from crushed tablets containing from crushedtablets containing 10/325 mg hydrocodone 10/325 mg hydrocodone Lotbitartrate/acetaminophen bitartrate/acetaminophen 1 14% 45% 2 60% 66%

Example 26(a): Assessment of Abuse by Multitablet Ingestion

The dosage form prepared according to Example 3 and 5 above wasevaluated for multiple tablet oral abuse resistance by stirring theselected number of tablets in 300 mL of 0.1N HCl. Dissolution wasperformed using USP Apparatus II at 50 rpm and 37° C. One to twelvetablets were added to the vessel simultaneously and aliquots wereremoved after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of agitationand analyzed for hydrocodone bitartrate (FIG. 4) and APAP (FIG. 5) byHPLC. The results were plotted against time and appear in FIGS. 4 and 5.

Example 26(b): Assessment of Abuse by Multitablet Ingestion

The dosage form prepared according to Example 17 above was evaluated formultiple tablet oral abuse resistance by stirring the selected number oftablets in 300 mL of 0.1N HCl. Dissolution was performed using USPApparatus II at 50 rpm and 37° C. One to twelve tablets were added tothe vessel simultaneously and aliquots were removed after 5, 10, 15, 30,60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodonebitartrate (FIG. 6) and APAP (FIG. 7) by HPLC. The results were plottedagainst time and appear in FIGS. 6 and 7.

Example 26(c): Assessment of Abuse by Multitablet Ingestion

The dosage form prepared according to Example 17 above was evaluated formultiple tablet oral abuse resistance by stirring the selected number oftablets in 300 mL of 0.1N HCl. Dissolution was performed using USPApparatus II at 50 rpm and 37° C. One to twelve tablets were added tothe vessel simultaneously and aliquots were removed after 5, 10, 15, 30,60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodonebitartrate and APAP by HPLC. The results were plotted against time andappear in FIG. 8 (hydrocodone bitartrate) and FIG. 9 (APAP).

Example 27: Coated Esketamine Granules

Coated esketamine granules are prepared as per the process described inExample 1 with slight variation from Example 1 in components asillustrated below.

TABLE 60 Esketamine hydrochloride granule compositions % w/w GranulationHypromellose 60 glyceryl behenate 26 Ethylcellulose 14 TOTAL 100Layering esketamine hydrochloride 5 polymer granules (EC, HPMC andCompritol) 92.5 Hypromellose 2910 2.5 TOTAL 100 Coating esketaminelayered granules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 28: Esketamine HCl Tablets

The coated granules prepared per Example 27 above are subsequently mixedwith other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose) and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and theresulting mixture was blended for additional 5 minutes prior tocompressing into tablets.

TABLE 61 Esketamine hydrochloride tablet compositions Components mg/tab1 mg 2 mg 5 mg 10 mg Hypromellose 11.1 22.2 55.6 111.2 glyceryl behenate4.8 9.5 23.8 47.64 Ethylcellulose 2.6 5.2 13.1 26.2 esketaminehydrochloride 1 2 5 10 Hypromellose 2910 0.5 1 2.5 5 Eudragit E-100 13.326.7 66.7 133.4 mannitol 70 70 70 70 carbopol 50 50 50 50microcrystalline cellulose 94 95 95 94 Crospovidone 90 90 95 150 sodiumbicarbonate 30 30 30 30 magnesium stearate 11 18 38.6 74.6 Total TabletWeight 378.3 419.6 545.3 802.04

Example 29: Coated Esketamine Granules

Coated esketamine granules are prepared as per the process described inExample 1 with slight variation from Example 1 in components asillustrated in the Table below.

TABLE 62 Esketamine hydrochloride coated granule compositions % w/wGranulation hypromellose 60 glyceryl behenate 26 ethyl cellulose 14TOTAL 100 Layering esketamine hydrochloride 10 polymer granules (EC,HPMC and Compritol) 85 hypromellose 2910 5 TOTAL 100 Coating esketaminelayered granules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 30: Esketamine HCl Tablets

Coated granules prepared per Example 29 above are subsequently mixedwith other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose) and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and theresulting mixture was blended for additional 5 minutes prior tocompressing into tablets.

TABLE 63 Esketamine hydrochloride tablet composition Components (mg/tab)14 mg Hypromellose 71.5 glyceryl behenate 30.6 ethyl cellulose 16.9esketamine hydrochloride 14 Hypromellose 2910 7 Eudragit E-100 93.4mannitol 70 Carbopol 50 microcrystalline cellulose 130 Crospovidone 150sodium bicarbonate 30 magnesium stearate 55 Total Tablet Weight 718.4

Example 31: Coated Esketamine Granules

Esketamine granules are manufactured using a process similar to thatdescribed in Example 1 above with some modification to the process. Theactive ingredient instead of being layered on the granules resides inthe core where it is granulated with other excipients as per the Tablebelow, and is subsequently coated with Eudragit E-100.

Granules are manufactured in a high shear granulator where hypromellose,Esketamine hydrochloride and glyceryl behenate are dry mixed for 3minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowlyadded while maintaining the granulator impeller and chopper speed atpre-selected values that provide enough shear for granule formation andgrowth. Solution addition is continued until the entire amount ofethylcellulose is added. The granules are then wet milled using a sizereduction mill (Granumill) and subsequently loaded into fluid bed fordrying.

Esketamine hydrochloride granules are then coated in a bottom sprayfluid bed coater with 25% alcoholic suspension of Eudragit E-100copolymer and magnesium stearate (2:1). The coated granules aresubsequently used in blending and compression process.

TABLE 64 Esketamine hydrochloride granule composition % w/w Granulationesketamine hydrochloride 35 hypromellose 45 glyceryl behenate 12.5ethylcellulose 7.5 Total 100 Coating esketamine granules 82 EudragitE-100 12 magnesium stearate 6 TOTAL 100

Example 32: Esketamine HCl Tablets

Coated granules prepared per Example 31 above are subsequently mixedwith other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose) and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and theresulting mixture was blended for additional 5 minutes prior tocompressing into tablets.

TABLE 65 Esketamine hydrochloride tablet composition Components(mg/tablet) 28 mg 56 mg 84 mg hypromellose 36 72 108 glyceryl behenate10 20 30 ethylcellulose 6 12 18 esketamine hydrochloride 28 56 84Eudragit E-100 11.7 23.4 35.1 mannitol 17 17 20.1 carbopol 50 50 50microcrystalline cellulose 100 100 100 crospovidone 150 150 150 sodiumbicarbonate 30 30 30 magnesium stearate 12 20 30 Total Tablet Weight450.7 550.4 655.2

Example 33: Coated Esketamine Granules

Esketamine granules are manufactured using a process similar to thatdescribed in Example 1 and Example 32 above with some modification tothe process. The active ingredient, is granulated with other excipientsper the table below, and is subsequently coated with Eudragit E-100.

Granules containing Esketamine hydrochloride are manufactured in a highshear granulator where hypromellose, esketamine hydrochloride andglyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholicsolution of ethylcellulose is slowly added while maintaining thegranulator impeller and chopper speed at pre-selected values thatprovide enough shear for granule formation and growth. Solution additionis continued until the entire amount of ethylcellulose is added. Thegranules are then wet milled using a size reduction mill (Granumill) andthen loaded into fluid bed for drying.

The granules are then coated in a bottom spray fluid bed coater with 25%alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate(2:1). The resulting coated granules are subsequently used for blendingand compression process.

TABLE 66 Esketamine hydrochloride granule composition % w/w Granulationesketamine hydrochloride 72.5 Hypromellose 17.5 glyceryl behenate 5Ethylcellulose 5 TOTAL 100 Coating esketamine granules 82 Eudragit E-10012 magnesium stearate 6 Total 100

Example 34: Esketamine HCl Tablets

The coated granules prepared per Example 33 above are subsequently mixedwith other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 67 Esketamine hydrochloride tablet compositions Components(mg/tab) 200 mg 300 mg 400 mg Hypromellose 48 72 96.4 glyceryl behenate14 21 27.6 ethyl cellulose 14 21 27.6 esketamine hydrochloride 200 300400 Eudragit E-100 40 61 81 Mannitol 25 25 25 Carbopol 75 75 75microcrystalline cellulose 125 125 125 Crospovidone 300 300 300 sodiumbicarbonate 45 45 45 magnesium stearate 140 150 160 Total Tablet Weight1026 1195 1362.6

Example 35: Coated Zolpidem Granules

Coated Zolpidem tartrate granules are prepared as per the processdescribed in Example 1 as per the composition illustrated in the Tablebelow.

TABLE 68 Zolpidem tartrate granule compositions % w/w GranulationHypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100Layering zolpidem tartrate 10 polymer granules (EC, HPMC and Compritol)85 Hypromellose 2910 5 TOTAL 100 Coating zolpidem layered granules 50Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 36: Zolpidem Tartrate Tablets

Coated zolpidem granules are prepared as per the process described inExample 35 above. The coated granules are mixed with other components(carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose and blended in a V-blender for 30 minutes. Magnesium stearateis added to lubricate the blend and blended for additional 5 minutesprior to compressing into tablets.

TABLE 69 Zolpidem tartrate tablet compositions Components (mg/tab) 5 mg10 mg hypromellose 25.5 51.1 glyceryl behenate 11 21.9 ethylcellulose 612 zolpidem tartrate 5 10 Hypromellose 2910 2.5 5 Eudragit E-100 33.466.7 mannitol 70 70 carbopol 50 50 microcrystalline cellulose 95 94crospovidone 100 100 sodium bicarbonate 30 30 magnesium stearate 21.639.3 Total Tablet Weight 450 550

Example 37: Coated Quetiapine Fumarate Granules

Quetiapine granules are manufactured using a process similar to thatdescribed in Example 1 above with some modification to the process. TheQuetiapine fumarate, instead of being layered on the granules, residesin the core where it granulated along with other excipients per Table 70(Granulation) and is subsequently coated with Eudragit E-100 andmagnesium stearate.

Granules are manufactured in a high shear granulator where hypromellose,Quetiapine fumarate, a portion of the Lutrol, sodium lauryl sulphate andglyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholicsolution of ethylcellulose is slowly added while maintaining thegranulator impeller and chopper speed at pre-selected values thatprovide enough shear for granule formation and growth. Solution additionis continued until the entire amount of ethylcellulose is added. Thegranules are then wet milled using a size reduction mill (Granumill) andthen loaded into fluid bed for drying.

The quetiapine fumarate granules are then coated in a bottom spray fluidbed coater with alcoholic suspension of Eudragit E-100 copolymer andmagnesium stearate. The resulting coated granules are then used inblending and compression process.

TABLE 70 Quetiapine fumarate coated granule composition % w/wGranulation quetiapine fumarate 23.7 Hypromellose 37.6 glyceryl behenate13.4 ethyl cellulose 8.1 sodium lauryl sulphate 9.1 Lutrol 8.1 TOTAL 100Coating quetiapine granules 62.5 Eudragit E-100 25 magnesium stearate12.5 TOTAL 100

Example 38: Quetiapine Fumarate Tablets

The coated granules prepared per Example 37 above are subsequently mixedwith other components (carbomer, crospovidone, remaining portion ofLutrol, sodium bicarbonate, mannitol, microcrystalline cellulose), andblended in a V-blender for 30 minutes. Magnesium stearate is added tolubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 71 Quetiapine fumarate tablet compositions 25 mg 50 mg 100 mgComponents (mg/tablet) (mg/tablet) (mg/tablet) (mg/tablet) hypromellose16 32 63 glyceryl behenate 9 18 36 Ethylcellulose 5 11 22 quetiapinefumarate 25 50 100 Eudragit E-100 27 53 107 Mannitol 17 17 20.1 Carbopol50 50 50 microcrystalline cellulose 100 100 100 Crospovidone 150 150 200sodium bicarbonate 30 30 30 magnesium stearate 18 31 63 Lutrol 45 51 62sodium lauryl sulphate 6 12 24 Total Tablet Weight 498 605 877.1

Example 39: Coated Quetiapine Granules

Quetiapine granules are manufactured using a process similar to thatdescribed in Example 1 and with some modification to the process. TheQuetiapine fumarate, instead of being layered on the granules, residesin the core where it is granulated along with other excipients per Table72 and is subsequently coated with Eudragit E-100.

Granules are manufactured in a high shear granulator where hypromellose,Quetiapine fumarate, sodium lauryl sulphate, portion of Lutrol andglyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholicsolution of ethylcellulose is slowly added while maintaining thegranulator impeller and chopper speed at pre-selected values thatprovide enough shear for granule formation and growth. Solution additionis continued until the entire amount of ethylcellulose is added. Thegranules are then wet milled using a size reduction mill (Granumill) andthen loaded into fluid bed for drying.

Quetiapine Fumarate granules are then coated in a bottom spray fluid bedcoater with alcoholic suspension of Eudragit E-100 copolymer andmagnesium stearate. The resultant coated granules are subsequently usedfor blending and compression process.

TABLE 72 Quetiapine fumarate granule compositions % w/w Granulationquetiapine fumarate 14.3 Hypromellose 59.2 glyceryl behenate 4.1Ethylcellulose 4.1 sodium lauryl sulphate 10.1 Lutrol 8.2 TOTAL 100Coating quetiapine granules 82 Eudragit E-100 12 magnesium stearate 6TOTAL 100

Example 40: Quetiapine Fumarate Tablets

The coated granules prepared as per Example 39 above are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose, and remaining portion of Lutrol)and blended in a V-blender for 30 minutes. Magnesium stearate is addedto lubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 73 Quetiapine fumarate tablet compositions Components (mg/tab) 200mg 300 mg 400 mg hypromellose 48 72.5 97 glyceryl behenate 14 20.8 28ethyl cellulose 14 20.8 28 quetiapine fumarate 200 300 400 EudragitE-100 40 74 99 mannitol 25 25 25 carbopol 50 65 65 microcrystallinecellulose 125 125 125 crospovidone 200 275 275 sodium bicarbonate 45 4545 magnesium stearate 36 48 64 Lutrol 78 91.6 105 sodium lauryl sulphate34 51.2 69 Total Tablet Weight 909 1213.9 1425

Example 41: Coated Hydromorphone Granules

Coated hydromorphone granules are prepared as per the process describedin Example 1 with slight variation from Example 1 in components asillustrated below.

TABLE 74 Hydromorphone hydrochloride granule composition % w/wGranulation Hypromellose 60 glyceryl behenate 26 ethyl cellulose 14TOTAL 100 Layering hydromorphone hydrochloride 5 polymer granules (EC,HPMC and Compritol) 92.5 Hypromellose 2910 2.5 TOTAL 100 Coatinghydromorphone layered granules 50 Eudragit E-100 33 magnesium stearate17 TOTAL 100

Example 42: Hydromorphone Hydrochloride Tablets

Coated hydromorphone granules are prepared as per the process describedin Example 1 and Example 41 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 75 Hydromorphone hydrochloride tablet compositions Components(mg/tablet) 2 mg 4 mg 8 mg hypromellose 22.2 44.4 88.9 glyceryl behenate9.5 19.1 38.1 ethyl cellulose 5.2 10.5 21 hydromorphone hydrochloride 24 8 Hypromellose 2910 1 2 4 Eudragit E-100 26.7 53.4 106.7 mannitol 7070 70 carbopol 50 50 50 microcrystalline cellulose 95 95 94 crospovidone90 95 150 sodium bicarbonate 30 30 30 magnesium stearate 18.1 58.3 60.4Total Tablet Weight 419.7 531.7 721.1

Example 43: Coated Methamphetamine Granules

Coated methamphetamine granules are prepared according to the processdescribed in Example 1.

TABLE 76 Methamphetamine hydrochloride granule composition % w/wGranulation Hypromellose 60 glyceryl behenate 26 ethyl cellulose 14TOTAL 100 Layering methamphetamine hydrochloride 5 polymer granules (EC,HPMC and Compritol) 92.5 Hypromellose 2910 2.5 TOTAL 100 Coatingmethamphetamine layered granules 50 Eudragit E-100 33 magnesium stearate17 TOTAL 100

Example 44: Methamphetamine Hydrochloride Tablets

Coated methamphetamine granules are prepared as per the processdescribed in Example 1 and Example 43 above. The coated granules aresubsequently mixed with other components (carbomer, crospovidone, sodiumbicarbonate, mannitol, microcrystalline cellulose), and blended in aV-blender for 30 minutes. Magnesium stearate is added to lubricate theblend and blended for additional 5 minutes prior to compressing intotablets.

TABLE 77 Methamphetamine hydrochloride tablet composition Components(mg/tablet) 5 mg hypromellose 55.6 glyceryl behenate 23.8 ethylcellulose 13.1 methamphetamine hydrochloride 5 Hypromellose 2910 2.5Eudragit E-100 66.7 mannitol 70 Carbopol 50 microcrystalline cellulose95 Crospovidone 100 sodium bicarbonate 30 magnesium stearate 39 TotalTablet Weight 550.7

Example 45: Coated Oxymorphone Granules

Coated oxymorphone granules are prepared as per the process described inExample 1.

TABLE 78 Oxymorphone hydrochloride granule composition % w/w GranulationHypromellose 60 glyceryl behenate 26 ethyl cellulose 14 TOTAL 100Layering oxymorphone hydrochloride 10 polymer granules (EC, HPMC andCompritol) 85 Hypromellose 2910 5 TOTAL 100 Coating oxymorphone layeredgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 46: Oxymorphone Hydrochloride Tablets

Coated oxymorphone granules are prepared as per the process described inExample 1 and Example 45 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 79 Oxymorphone hydrochloride tablet compositions Components(mg/tablet) 5 mg 10 mg Hypromellose 25.5 51.1 glyceryl behenate 11 21.9ethyl cellulose 6 12 oxymorphone hydrochloride 5 10 Hypromellose 29102.5 5 Eudragit E-100 33.4 66.7 Mannitol 70 70 carbopol 45 45microcrystalline cellulose 95 94 Crospovidone 100 100 sodium bicarbonate27 27 magnesium stearate 21.6 39.3 Total Tablet Weight 442 542

Example 47: Coated Oxycodone Granules

Coated oxycodone granules are prepared as per the process described inExample 1.

The composition for the coated oxycodone granules is provided in Table80 below.

TABLE 80 Oxycodone hydrochloride granule composition % w/w GranulationHypromellose 60 glyceryl behenate 26 Ethylcellulose 14 TOTAL 100Layering oxycodone hydrochloride 10 polymer granules (EC, HPMC andCompritol) 85 Hypromellose 2910 5 TOTAL 100 Coating oxycodone layeredgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 48: Oxycodone Hydrochloride Tablets

Coated oxycodone granules are prepared as per the process described inExample 1 and Example 47 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 81 Oxycodone hydrochloride tablet compositions Components(mg/tablet) 5 mg 15 mg 30 mg hypromellose 25.5 76.6 153.3 glycerylbehenate 11 32.8 65.7 ethyl cellulose 6 18.1 36.1 oxycodonehydrochloride 5 15 30 Hypromellose 2910 2.5 7.5 15 Eudragit E-100 33.4100.1 200.1 mannitol 70 37.29 70 carbopol 45 50 50 microcrystallinecellulose 95 130 94 crospovidone 100 150 200 sodium bicarbonate 27 30 30magnesium stearate 21.6 57 110 Total Tablet Weight 442 704.39 1054.2

Example 49: Coated Morphine Sulphate Granules

Coated morphine granules are prepared as per the process described inExample 1.

TABLE 82 Morphine Sulfate tablet compositions % w/w Granulationhypromellose 60 glyceryl behenate 26 ethyl cellulose 14 TOTAL 100Layering morphine sulphate 10 polymer granules (EC, HPMC and Compritol)85 Hypromellose 2910 5 TOTAL 100 Coating morphine layered granules 50Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 50: Morphine Sulphate Tablets

Coated morphine granules are prepared as per the process described inExample 1 and Example 49 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 83 Morphine sulphate tablet compositions Components (mg/tablet) 6mg 15 mg 30 mg hypromellose 30.6 76.6 153.3 glyceryl behenate 13.1 32.865.7 ethyl cellulose 7.2 18.1 36.1 morphine sulphate 6 15 30Hypromellose 2910 3 7.5 15 Eudragit E-100 40.02 100.1 200.1 mannitol 7070 70 carbopol 45 50 50 microcrystalline cellulose 95 130 94Crospovidone 100 150 200 sodium bicarbonate 27 30 30 magnesium stearate24.5 57 110 Total Tablet Weight 461.42 737.1 1054.2

Example 51: Coated Mixed Amphetamine Salts Granules

Coated granules containing mixed amphetamine salts (dextroamphetaminesaccharate, amphetamine aspartate, dextroamphetamine sulfate,amphetamine sulfate) are prepared as per the process described inExample 1.

TABLE 84 Mixed amphetamine salt granule formulation % w/w GranulationHypromellose 60 glyceryl behenate 26 ethyl cellulose 14 TOTAL 100Layering Mixed amphetamine salts (*Dextroamphetamine saccharate, 10amphetamine aspartate) polymer granules (EC, HPMC and Compritol) 85Hypromellose 2910 5 TOTAL 100 Coating mixed amphetamine salt layeredgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 52: Mixed Amphetamine Salt Tablets

Coated granules containing mixed amphetamine salts are prepared as perthe process described in Example 1 and Example 51 above. The coatedgranules are subsequently mixed with other components such as carbomer,crospovidone, sodium bicarbonate, mannitol, microcrystalline celluloseand blended in a V-blender for 30 minutes. Magnesium stearate is addedto lubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 85 Mixed amphetamine salt tablet formulation TotalAmphetamine/Base Equivalence 3.13 mg 4.7 mg 6.3 mg 7.8 mg 9.4 mg 12.6 mg18.8 mg Components (mg/tablet) 5 mg 7.5 mg 10 mg 12.5 mg 15 mg 20 mg 30mg hypromellose 25.5 38.3 51.1 63.8 76.6 102.15 153.3 glyceryl behenate10.9 16.4 21.9 27.4 32.8 43.8 65.7 ethyl cellulose 6.02 9.03 12.04 15.0518.1 24.1 36.1 Mixed amphetamine salts* 5 7.5 10 12.5 15 20 30Hypromellose 2910 2.5 3.75 5 6.25 7.5 10 15 Eudragit E-100 33.4 50.0466.7 83.4 100.1 133.4 200.1 mannitol 70 70 70 70 70 70 70 carbopol 45 4545 50 50 50 50 microcrystalline 95 95 95 130 130 130 150 cellulosecrospovidone 100 100 100 150 150 160 200 sodium bicarbonate 27 27 27 3030 30 30 magnesium stearate 21.5 30 38.6 48 57 75 110 Total TabletWeight 441.82 492.02 542.34 686.4 737.1 848.45 1110.2 *dextroamphetaminesaccharate, amphetamine aspartate monohydrate equivalent,dextroamphetamine sulfate, amphetamine sulfate.

Example 53: Codeine Phosphate Granules

Coated granules containing Codeine phosphate are prepared as per theprocess described in Example 1 with some modifications to thecomposition as described below.

TABLE 86 Codeine phosphate granule formulation % w/w GranulationHypromellose 60 glyceryl behenate 26 ethyl cellulose 14 TOTAL 100Layering codeine phosphate. 20 polymer Granules (EC, HPMC and Compritol)70 Hypromellose 2910 10 TOTAL 100 Coating codeine phosphate layeredgranules 70 Eudragit E-100 20 magnesium stearate 10 TOTAL 100

Example 54: Codeine Phosphate Tablets

Coated granules containing codeine phosphate are prepared as per theprocess described in Example 1 and Example 53 above. The coated granulesare subsequently mixed with other active ingredient (paracetamol), andother components (carbomer, crospovidone, sodium bicarbonate, mannitol,colorant, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 87 Codeine phosphate/APAP tablet formulation Components(mg/tablet) 30/300 mg 60/300 mg hypromellose 63.1 126.2 glycerylbehenate 27 54.1 ethyl cellulose 14.9 29.7 codeine phosphate 30 60Hypromellose 2910 15 30 Eudragit E-100 42.9 85.7 paracetamol* 315.8315.8 mannitol 29.4 29.4 Carbopol 50 50 microcrystalline cellulose 180180 Crospovidone 200 200 sodium bicarbonate 30 30 FD&C blue # 2 NA 0.6Iron Oxide Yellow 510P 0.5 NA magnesium stearate 31.5 57 Total TabletWeight 1030.1 1248.5 *The paracetamol grade Contains 300 mg of APAP and15.8 mg of gelatin

Example 55: Methylphenidate Hydrochloride Granules

Coated granules containing methylphenidate hydrochloride are prepared asper the process described in Example 1.

TABLE 88 Methylphenidate hydrochloride granule formulation % w/wGranulation Hypromellose 60 glyceryl behenate 26 ethyl cellulose 14TOTAL 100 Layering methylphenidate hydrochloride 10 polymer granules(EC, HPMC and 85 Compritol) Hypromellose 2910 5 TOTAL 100 Coatingmethylphenidate hydrochloride layered 50 granules Eudragit E-100 33magnesium stearate 17 TOTAL 100

Example 56: Methylphenidate Hydrochloride Tablets

Coated granules containing methylphenidate hydrochloride are prepared asper the process described in Example 1 and Example 55 above. The coatedgranules are subsequently mixed with other components (carbomer,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose),and blended in a V-blender for 30 minutes. Magnesium stearate is addedto lubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 89 Methylphenidate hydrochloride tablet formulation Components(mg/tablet) 5 mg 20 mg hypromellose 25.5 102.15 glyceryl behenate 10.943.8 ethyl cellulose 6.02 24.1 methylphenidate hydrochloride 5 20Hypromellose 2910 2.5 10 Eudragit E-100 33.4 133.4 Mannitol 70 70Carbopol 45 50 microcrystalline cellulose 95 150 Crospovidone 100 160sodium bicarbonate 27 30 magnesium stearate 21.5 75 Total Tablet Weight441.82 868.45

Example 57: Oxycodone Hydrochloride Granules

Coated granules containing oxycodone hydrochloride were prepared andcoated as per the process described in Example 1.

TABLE 90 Oxycodone hydrochloride granule formulation % w/w GranulationHypromellose 60 glyceryl behenate 26 ethyl cellulose 14 TOTAL 100Layering oxycodone hydrochloride 10 polymer granules (EC, HPMC and 85Compritol) Hypromellose 2910 5 TOTAL 100 Coating oxycodone layeredgranules, 10% 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Granules were manufactured in a high shear granulator where Hypromelloseand glyceryl behenate were dry mixed for 3 minutes. Then a 10%hydroalcoholic solution of ethylcellulose N10 was slowly added whilemaintaining the granulator impeller and chopper speed at pre-selectedvalues that provide enough shear for granule formation and growth.Solution addition was continued until the entire amount ofethylcellulose was added. The granules were then wet milled using a sizereduction mill (Granumill) and were subsequently loaded into fluid bedfor drying. The prepared granules were then layered in a bottom sprayfluid bed coater with a 12% aqueous solution of oxycodone hydrochlorideand HPMC 2910 (2:1).

The oxycodone hydrochloride layered granules were then coated in abottom spray fluid bed coater with 25% alcoholic suspension of EudragitE-100 copolymer and magnesium stearate (2:1). The resulting coatedgranules were subsequently used for further blending and compressionprocess.

Example 58: Oxycodone/Acetaminophen Tablets

The coated granules prepared according to the example 57 above weremixed with another active agent, Paracetamol, and other excipients(carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue,microcrystalline cellulose), and blended in a V-blender for 30 minutes.Magnesium stearate was then added to lubricate the blend and blended foradditional 5 minutes prior to compressing into oxycodone/APAP tablets.

TABLE 91 Oxycodone hydrochloride tablet formulation Component % w/woxycodone coated granules 20.0 paracetamol* 33.7 Mannitol 4.2 carbopol5.0 microcrystalline cellulose 13.0 Crospovidone 20.0 sodium bicarbonate3.0 FD&C blue 0.06 magnesium stearate 1.0 Total 100 *Contains 95%acetaminophen and 5% gelatin

Example 59: Oxycodone/Acetaminophen Tablets

The coated granules prepared according to the example 57 above weremixed with another active agent, Paracetamol, and other excipients(carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue,microcrystalline cellulose), and blended in a V-blender for 30 minutes.Magnesium stearate was then added to lubricate the blend and blended foradditional 5 minutes prior to compressing into oxycodone/APAP tablets.

TABLE 92 Oxycodone/acetaminophen tablet formulations Component (% w/w)5/325 mg 7.5/325 mg 10/325 mg oxycodone coated granules 12.5 16.7 20.0paracetamol* 42.8 38.0 34.2 Mannitol 3.7 4.37 3.79 carbopol 6.25 5.6 5microcrystalline cellulose 12 12 13 Crospovidone 18 19 20 sodiumbicarbonate 3.75 3.3 3 Iron Oxide yellow 0.06 NA NA FD&C Blue # 2 NA0.06 NA magnesium stearate 1.0 1.0 1.0 Total 100 100 100 *Contains 95%acetaminophen and 5% gelatin

Example 60: Armodafinil Granules

Armodafinil granules are manufactured using a process similar to thatdescribed in Example 1 and with some modification to the process. Theactive ingredient, Armodafinil, instead of being layered on thegranules, resides in the core where it is granulated along with otherexcipients as per Table 93, and is subsequently coated with EudragitE-100.

Granules are manufactured in a high shear granulator where hypromellose,Armodafinil, povidone and glyceryl behenate are dry mixed for 3 minutes.Then a 10% hydroalcoholic solution of ethylcellulose is slowly addedwhile maintaining the granulator impeller and chopper speed atpre-selected values that provide enough shear for granule formation andgrowth. Solution addition is continued until the entire amount ofethylcellulose is added. The granules are then wet milled using a sizereduction mill (Granumill) and subsequently loaded into fluid bed fordrying.

Armodafinil granules are then coated in a bottom spray fluid bed coaterwith alcoholic suspension of Eudragit E-100 copolymer and magnesiumstearate. The resultant coated granules are subsequently used forblending and compression process.

TABLE 93 Armodafinil granule formulations % w/w Granulation Armodafinil66.99 Hypromellose 16.75 glyceryl behenate 3.83 ethyl cellulose 3.83Povidone 8.61 TOTAL 100 Coating armodafinil granules 70 Eudragit E-10020 magnesium stearate 10 TOTAL 100

Example 61: Armodafinil Tablets

The coated granules prepared as per Example 60 above are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 94 Armodafinil tablet formulations 50 mg 150 mg 200 mg Components(mg/tablet) (mg/tablet) (mg/tablet) (mg/tablet) hypromellose 12.5 37.550 glyceryl behenate 2.9 8.6 11 ethyl cellulose 2.9 8.6 11 armodafinil50 150 200 Eudragit E-100 21.3 64 85 mannitol 17 25 25 carbopol 50 50 50microcrystalline cellulose 100 125 125 crospovidone 150 200 200 sodiumbicarbonate 30 30 30 magnesium stearate 16 40 52 povidone 6.4 19.3 26Total Tablet Weight 459 758 865

Example 62: Phenobarbital Granules

Phenobarbital granules are manufactured using a process similar to thatdescribed in Example 1 and with some modification to the process. Theactive ingredient, Phenobarbital, instead of being layered on thegranules, resides in the core where it is granulated along with otherexcipients per the Table below, and is subsequently coated with EudragitE-100.

Granules are manufactured in a high shear granulator where hypromellose,phenobarbital, povidone and glyceryl behenate are dry mixed for 3minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowlyadded while maintaining the granulator impeller and chopper speed atpre-selected values that provide enough shear for granule formation andgrowth. Solution addition is continued until the entire amount ofethylcellulose is added. The granules are then wet milled using a sizereduction mill (Granumill) and subsequently loaded into fluid bed fordrying.

The phenobarbital granules are then coated in a bottom spray fluid bedcoater with alcoholic suspension of Eudragit E-100 copolymer andmagnesium stearate. The resultant coated granules are subsequently usedfor blending and compression process.

TABLE 95 Phenobarbital granule formulations % w/w GranulationPhenobarbital 66.99 Hypromellose 16.75 glyceryl behenate 3.83 ethylcellulose 3.83 Povidone 8.61 TOTAL 100 Layering phenobarbital granules50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 63: Phenobarbital Tablets

The coated granules prepared as per Example 62 above are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 96 Phenobarbital tablet formulations 15 mg 30 mg 60 mg 100 mgComponents (mg/tablet) (mg/tablet) (mg/tablet) (mg/tablet) hypromellose3.8 7.5 15 25.01 glyceryl 1 2 3.4 5.72 behenate ethyl cellulose 1 2 3.45.72 phenobarbital 15 30 60 100 Eudragit E-100 15 30 59 98.5 mannitol 2020 20 20 carbopol 50 50 50 50 microcrys- 75 100 100 100 tallinecellulose crospovidone 130 130 200 200 sodium 30 30 30 30 bicarbonatemagnesium 12 20 36 59 stearate povidone 2 4 7.7 12.9 Total Tablet 354.8425.5 584.5 706.85 Weight

Example 64: Diazepam Granules

Coated diazepam granules are prepared as per the process described inExample 1 with slight variation from Example 1 in components asillustrated in the Table below.

TABLE 97 Diazepam granule formulations % w/w Granulation Hypromellose 60glyceryl behenate 26 ethyl cellulose 14 TOTAL 100 Layering diazepam 5polymer granules (EC, HPMC and Compritol) 92.5 Hypromellose 2910 2.5TOTAL 100 Coating diazepam layered granules 50 Eudragit E-100 33magnesium stearate 17 TOTAL 100

Example 65: Diazepam Tablets

Coated diazepam granules are prepared as per the process described inExample 1 and Example 64 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 98 Diazepam tablet formulations Components (mg/tablet) 2 mg 5 mg10 mg Hypromellose 22.2 55.6 111.2 glyceryl behenate 9.5 23.8 47.64ethyl cellulose 5.2 13.1 26.2 Diazepam 2 5 10 Hypromellose 2910 1 2.5 5Eudragit E-100 26.7 66.7 133.4 mannitol 70 70 70 carbopol 50 50 50microcrystalline cellulose 95 95 94 Crospovidone 120 120 150 sodiumbicarbonate 30 30 30 magnesium stearate 18.1 38.6 74.6 Total TabletWeight 449.7 570.3 802.04

Example 66: Hydrocodone Bitartrate Granules

Coated granules containing hydrocodone bitartrate are prepared as perthe process described in Example 1.

TABLE 99 Hydrocodone bitartrate granule formulations % w/w GranulationHypromellose 60 glyceryl behenate 26 ethyl cellulose 14 TOTAL 100Layering hydrocodone bitartrate 10 polymer granules (EC, HPMC andCompritol) 85 Hypromellose 2910 5 TOTAL 100 Coating hydrocodonebitartrate layered granules 50 Eudragit E-100 33 magnesium stearate 17TOTAL 100

Example 67: Hydrocodone Bitartrate Tablets

Coated granules containing hydrocodone bitartrate are prepared as perthe process described in Example 1 and Example 66 above. The coatedgranules are subsequently mixed with other components (carbomer,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate is addedto lubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 100 Hydrocodone Tablet Formulations 5 mg 10 mg Components(mg/tablet) (mg/tablet) hypromellose 25.5 51.1 glyceryl behenate 11 21.9ethyl cellulose 6 12.04 hydrocodone bitartrate 5 10 Hypromellose 29102.5 5 Eudragit E-100 33.4 66.7 Mannitol 70 70 Carbopol 50 50microcrystalline cellulose 95 95 Crospovidone 100 120 sodium bicarbonate30 30 magnesium stearate 21.6 39.3 Total Tablet Weight 450 571.04

Example 68: Oxycodone Hydrochloride Coated Granules

TABLE 201 Granule Formulation Component % w/w Hypromellose K100M 60glyceryl behenate 26 ethyl cellulose (10 cps) 14 TOTAL 100

TABLE 102 Layered Granule Formulation Component % w/w oxycodonehydrochloride 10 polymer granules (EC, HPMC and Compritol) 85Hypromellose 2910 E3 5 TOTAL 100

TABLE 103 Coated Granules Formulation Component % w/w oxycodonehydrochloride layered granules, 10% 50 Eudragit E-100 33 magnesiumstearate 17 TOTAL 100

Granules were manufactured in a high shear granulator, wherehypromellose, glyceryl behenate, and a portion (67%) of theethylcellulose were dry mixed for 3 minutes. Then, a hydroalcoholic (˜28parts of water and ˜72 parts of alcohol) solution of ethylcellulose (10%wt/wt) was slowly added while maintaining the granulator impeller andchopper speed at pre-selected values that provide enough shear forgranule formation and growth. Solution addition was continued until theentire amount of ethylcellulose was added. The granules were then wetmilled using a size reduction mill (Granumill) and were subsequentlyloaded into fluid bed for drying.

The prepared granules were then layered in a bottom spray fluid bedcoater with a 12% wt/wt aqueous solution of oxycodone hydrochloride andHPMC.

The oxycodone bitartrate layered granules were then coated in a bottomspray fluid bed coater with 25% alcoholic suspension of Eudragit E-100copolymer and magnesium stearate. The resulting coated granules weresubsequently blended for homogeneity and used for further blending andcompression process.

Example 69: Oxycodone Acetaminophen Tablet Formation

Coated granules were prepared according to the Example 68 above, andmixed with Paracetamol (manufactured using acetaminophen and gelatin)and other excipients (as listed in Table 104 below), and blended forapproximately 270 revolutions. Magnesium stearate was then added tolubricate the blend and blended for additional 45 revolutions. The blendwas then compressed into oxycodone/acetaminophen tablets.

TABLE 104 Tablet Formulation Component % w/w mg/tablet Oxycodonehydrochloride coated granules, 5% 20.0 200 Paracetamol 33.7  337*Mannitol 10.3 103 Carbopol 5.0  50 microcrystalline cellulose 12.0 120Crospovidone 15.0 150 sodium bicarbonate 3.0  30 magnesium stearate 1.0 10 Total 100 1000  *contains 325 mg of acetaminophen

Example 70: Coated Oxycodone Granules, 5%

Granules were prepared, layered with API and subsequently coated. Thesecoated particles were then blended with other components and compressedinto tablets.

TABLE 305 Granules Formulation Component % w/w Hypromellose K100M 60Glyceryl behenate 26 Ethyl cellulose (10 cP) 14 TOTAL 100

TABLE 106 Layered Granules Formulation Component % w/w OxycodoneHydrochloride 10 Polymer granules (EC, HPMC and Compritol) 85Hypromellose 2910 (HPMC 2910 E3) 5 TOTAL 100

TABLE 107 Coated Granules Formulation Component % w/w Oxycodonehydrochloride layered granules, 10% 50 Eudragit E-100 33 Magnesiumstearate 17 TOTAL 100

Granules were manufactured in a high shear granulator, wherehypromellose, a portion of ethyl cellulose and glyceryl behenate weredry mixed for 3 minutes. Then a 10% w/w hydroalcoholic (˜28 parts ofwater and ˜72 parts of ethanol) solution of ethyl cellulose 10 cP wasslowly added while maintaining the granulator impeller and chopper speedat pre-selected values that provide enough shear for granule formationand growth. Solution addition was continued until the entire amount ofethyl cellulose was added. The granules were then wet milled using asize reduction mill (Granumill) and were subsequently loaded into fluidbed for drying.

The prepared granules were then layered in a bottom spray fluid bedcoater with a 12% w/w aqueous solution of oxycodone hydrochloride andHPMC 2910 E3.

The oxycodone hydrochloride layered granules were then coated in abottom spray fluid bed coater with 25% alcoholic suspension of EudragitE-100 copolymer and magnesium stearate. The resulting coated granuleswere subsequently blended for homogeneity and used for further blendingand compression process.

Example 71: Coated Polymer Granules

Granules were manufactured in a high shear granulator, wherehypromellose, a portion of ethyl cellulose and glyceryl behenate weredry mixed for 3 minutes. Then a 10% w/w hydroalcoholic (˜28 parts ofwater and ˜72 parts of ethanol) solution of ethyl cellulose 10 cP wasslowly added while maintaining the granulator impeller and chopper speedat pre-selected values that provide enough shear for granule formationand growth. Solution addition was continued until the entire amount ofethyl cellulose was added. The granules were then wet milled using asize reduction mill (Granumill) and were subsequently loaded into fluidbed for drying.

The granules were then coated in a bottom spray fluid bed coater with25% alcoholic suspension of Eudragit E-100 copolymer and magnesiumstearate.

TABLE 108 Granules Formulation Component % w/w Hypromellose K100M 60Glyceryl behenate 26 Ethyl cellulose (10 cP) 14 TOTAL 100

TABLE 109 Coated Polymer Granules Formulation Component % w/w Polymergranules 50 Eudragit E-100 33 Magnesium stearate 17 TOTAL 100

Example 72A and Example 72B

The oxycodone hydrochloride coated granules were prepared according tothe Example 70 and mixed with coated polymer granules prepared accordingto Example 71. Another active agent i.e. Paracetamol (manufactured usingacetaminophen and gelatin) and other excipients such as carbomer,crospovidone, sodium bicarbonate, mannitol and microcrystallinecellulose were added and blended for approximately 270 revolutions.Magnesium stearate was then added to lubricate the blend and blended foradditional 45 revolutions prior to compressing intooxycodone/acetaminophen tablets.

TABLE 110 Tablet Formulation Example 72A Example 72B Component % w/wmg/tablet % w/w mg/tablet Oxycodone hydrochloride 10.87 108.7  16.3 163coated granules, 5% Coated Polymer granules 9.13 91.3 3.7 37 Paracetamol33.7 337*   33.71 337.1* Mannitol 4.29 42.9 4.29 42.9 Carbopol 5.0 50.05.0 50 Microcrystalline cellulose 13.0 130.0  13.0 130 Crospovidone 20.0200.   20.0 200 Sodium bicarbonate 3.0 30   3.0 30 Magnesium stearate1.0 10   1.0 10 Total 100 1000    100 1000 *contains 325 mg ofacetaminophen

Example 73: In Vitro Analysis of Multiple Tablet Oral Abuse Resistance

The dosage form prepared according to Example 72A and Example 72B wasevaluated for in vitro multiple tablet oral abuse resistance by stirringthe selected number of tablets in 300 mL of 0.1N HCl. Dissolution wasperformed using USP apparatus II at 50 RPM and 37° C. One to twelvetablets were added to the vessel simultaneously and aliquots wereremoved periodically and analyzed for oxycodone hydrochloride (FIG. 10)and Acetaminophen (APAP) [FIG. 11] by HPLC. The results were plottedagainst time and appear in FIG. 10 and FIG. 11.

Example 74: Polymer Granules

TABLE 111 Granules Formulation Component % w/w Hypromellose K100M 60Glyceryl behenate 26 Ethyl cellulose (10 cP) 14 TOTAL 100

Granules were manufactured in a high shear granulator, wherehypromellose, a portion of ethyl cellulose and glyceryl behenate weredry mixed for 3 minutes. Then a 10% w/w hydroalcoholic (˜28 parts ofwater and ˜72 parts of ethanol) solution of ethyl cellulose 10 cP wasslowly added while maintaining the granulator impeller and chopper speedat pre-selected values that provide enough shear for granule formationand growth. Solution addition was continued until the entire amount ofethyl cellulose was added. The granules were then wet milled using asize reduction mill (Granumill) and were subsequently loaded into fluidbed for drying.

Example 75: Hydrocodone Bitartrate Coated Granules, 5%

The granules prepared according to Example 74 were then layered in abottom spray fluid bed coater with a 12% w/w aqueous solution ofhydrocodone bitartate and HPMC 2910 E3. The hydrocodone bitartratelayered granules were then coated in a bottom spray fluid bed coaterwith 25% alcoholic suspension of Eudragit E-100 copolymer and magnesiumstearate.

TABLE 112 Layered Granules Formulation Component % w/w Hydrocodonebitartrate 10 Polymer granules (EC, HPMC and Compritol) 85 Hypromellose2910 5 TOTAL 100

TABLE 113 Coated Granules Formulation Component % w/w Hydrocodonebitartrate layered granules, 10% 50 Eudragit E-100 33 Magnesium stearate17 TOTAL 100

Example 76: Hydrocodone Bitartrate Tablets

The hydrocodone bitartrate coated granules were prepared according tothe Example 75 above and mixed with polymer granules prepared accordingto Example 74. Another active agent i.e. Paracetamol (manufactured usingacetaminophen and gelatin) and other excipients such as carbomer,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulosewere added and blended for approximately 270 revolutions. Magnesiumstearate was then added to lubricate the blend and blended foradditional 45 revolutions prior to compressing intohydrocodone/acetaminophen tablets.

TABLE 114 Tablet Formulation Component % w/w mg/tablet Hydrocodonebitartrate coated granules, 5% 9.62 96.2 Polymer granules 5.38 53.8Paracetamol 33.71 337.1* Mannitol 9.29 92.9 Carbopol 5.0 50Microcrystalline cellulose 13.0 130 Crospovidone 20.0 200 Sodiumbicarbonate 3.0 30 Magnesium stearate 1.0 10 Total 100 1000 *contains325 mg of acetaminophen

Example 77A and Example 77B: Hydrocodone Bitartrate Tablets

The hydrocodone bitartrate coated granules, 5% were prepared accordingto the Example 75 above and mixed with coated polymer granules preparedaccording to Example 71. Another active agent i.e. Paracetamol(manufactured using acetaminophen and gelatin) and other excipients suchas carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose were added to the blender and blended forapproximately 270 revolutions. Magnesium stearate was then added tolubricate the blend and blended for additional 45 revolutions prior tocompressing into hydrocodone/acetaminophen tablets.

TABLE 115 Tablet Formulation Example 77A Example 77B Component % w/wmg/tab % w/w mg/tab Hydrocodone bitartrate coated 9.62 96.2 14.42 144.2granules, 5% Coated Polymer granules 10.38 103.8 5.58 55.8 Paracetamol33.71 337.1* 33.71 337.1* Mannitol 4.29 42.9 4.29 42.9 Carbopol 5.0 505.0 50 Microcrystalline cellulose 13.0 130 13.0 130 Crospovidone 20.0200 20.0 200 Sodium bicarbonate 3.0 30 3.0 30 Magnesium stearate 1.0 101.0 10 Total 100 1000 100 1000 *contains 325 mg of acetaminophen

Example 78: In Vitro Analysis of Multiple Tablet Oral Abuse Resistance

The dosage form prepared according to Example 76 and Example 77A andExample 77B was evaluated for in vitro multiple tablet oral abuseresistance by stirring the selected number of tablets in 300 mL of 0.1NHCl. Dissolution was performed using USP apparatus II at 50 RPM and 37°C. One to twelve tablets were added to the vessel simultaneously andaliquots were removed periodically and analyzed for hydrocodonebitartrate (FIG. 12) and APAP (FIG. 13) by HPLC. The results wereplotted against time and appear in FIG. 12 and FIG. 13.

Example 79: Coated Oxycodone Granules, 5%

Granules are prepared and subsequently coated. These coated particlesare then blended with other components and compressed into tablets.

TABLE 116 Granules Formulation Component % w/w Hypromellose K100M 54Glyceryl behenate 23 Ethyl cellulose (10 cP) 13 Oxycodone Hydrochloride10 TOTAL 100

TABLE 117 Coated Granules Formulation Component % w/w Oxycodonehydrochloride granules, 10% 50 Eudragit E-100 33 Magnesium stearate 17TOTAL 100

Granules are manufactured in a high shear granulator, where oxycodonehydrochloride, hypromellose, a portion of ethyl cellulose and glycerylbehenate is dry mixed for 3 minutes. Then a hydroalcoholic solution ofethyl cellulose 10 cP is slowly added while maintaining the granulatorimpeller and chopper speed at pre-selected values that provide enoughshear for granule formation and growth. Solution addition is continueduntil the entire amount of ethyl cellulose is added. The granules arethen wet milled using a size reduction mill (Granumill) and subsequentlyloaded into fluid bed for drying. The oxycodone hydrochloride granulesare then coated in a bottom spray fluid bed coater with 25% alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate.

Example 80: Oxycodone/Acetaminophen Tablets

The oxycodone hydrochloride coated granules, 5% are prepared accordingto the Example 79 above and mixed with another active agent i.e.Paracetamol (manufactured using acetaminophen and gelatin) and otherexcipients such as carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose and blended for approximately 270revolutions. Magnesium stearate is then added to lubricate the blend andblended for additional 45 revolutions prior to compressing intooxycodone/acetaminophen tablets.

TABLE 118 Tablet Formulation Component % w/w mg/tablet Oxycodonehydrochloride coated granules, 5% 20 200  Paracetamol 34.2 342* Mannitol3.8 38 Carbopol 5.0 50 Microcrystalline cellulose 13.0 130  Crospovidone20.0 200  Sodium bicarbonate 3.0 30 Magnesium stearate 1.0 10 Total 1001000  *contains 325 mg of acetaminophen

Example 81: Coated Oxycodone Granules

Oxycodone hydrochloride granules are prepared and subsequently coated.These coated particles are then blended with other components andcompressed into tablets.

TABLE 119 Granules Formulation Component % w/w Hypromellose K100M 56Glyceryl behenate 25 Ethyl cellulose (10 cP) 14 Oxycodone Hydrochloride5 TOTAL 100

TABLE 120 Coated Granules Formulation Component % w/w Oxycodonehydrochloride granules, 5% 50 Eudragit E-100 33 Magnesium stearate 17TOTAL 100

Granules are manufactured in a high shear granulator, where oxycodonehydrochloride, hypromellose, a portion of ethyl cellulose and glycerylbehenate is dry mixed for 3 minutes. Then a hydroalcoholic solution ofethyl cellulose 10 cP is slowly added while maintaining the granulatorimpeller and chopper speed at pre-selected values that provide enoughshear for granule formation and growth. Solution addition is continueduntil the entire amount of ethyl cellulose is added. The granules arethen wet milled using a size reduction mill (Granumill) and subsequentlyloaded into fluid bed for drying. The oxycodone hydrochloride granulesare then coated in a bottom spray fluid bed coater with 25% alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate.

Example 82: Oxycodone/Acetaminophen Tablets

The oxycodone hydrochloride coated granules, 2.5% are prepared accordingto the Example 81 above and mixed with another active agent i.e.Paracetamol (manufactured using acetaminophen and gelatin) and otherexcipients such as carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose and blended for approximately 270revolutions. Magnesium stearate is then added to lubricate the blend andblended for additional 45 revolutions prior to compressing intooxycodone/acetaminophen tablets.

TABLE 121 Tablet Formulation Component % w/w mg/tablet Oxycodonehydrochloride coated granules, 2.5% 20 200 Paracetamol 34.2 342 Mannitol3.8 38 Carbopol 5.0 50 Microcrystalline cellulose 13.0 130 Crospovidone20.0 200 Sodium bicarbonate 3.0 30 Magnesium stearate 1.0 10 Total 1001000 *contains 325 mg of acetaminophen

Example 83: Coated Oxycodone Granules

Oxycodone hydrochloride granules are prepared and subsequently coated.These coated particles are then blended with other components andcompressed into tablets.

TABLE 122 Granules Formulation Component % w/w Hypromellose K100M 54.5Glyceryl behenate 24 Ethyl cellulose (10 cP) 14 Oxycodone Hydrochloride7.5 TOTAL 100

TABLE 123 Coated Granules Formulation Component % w/w Oxycodonehydrochloride granules, 7.5% 50 Eudragit E-100 33 Magnesium stearate 17TOTAL 100

Granules are manufactured in a high shear granulator, where oxycodonehydrochloride, hypromellose, a portion of ethyl cellulose and glycerylbehenate is dry mixed for 3 minutes. Then a hydroalcoholic solution ofethyl cellulose 10 cP is slowly added while maintaining the granulatorimpeller and chopper speed at pre-selected values that provide enoughshear for granule formation and growth. Solution addition is continueduntil the entire amount of ethyl cellulose is added. The granules arethen wet milled using a size reduction mill (Granumill) and subsequentlyloaded into fluid bed for drying. The oxycodone hydrochloride granulesare then coated in a bottom spray fluid bed coater with 25% alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate.

Example 84: Oxycodone/Acetaminophen Tablets

The oxycodone HCl coated granules, 3.75% are prepared according toExample 83 above and mixed with another active agent i.e. Paracetamol(manufactured using acetaminophen and gelatin) and other excipients suchas carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose and blended for approximately 270revolutions. Magnesium stearate is then added to lubricate the blend andblended for additional 45 revolutions prior to compressing intooxycodone/acetaminophen tablets.

TABLE 124 Tablet Formulation Component % w/w mg/tablet Oxycodonehydrochloride coated granules, 3.75% 20 200  Paracetamol 34.2 342*Mannitol 3.8 38 Carbopol 5.0 50 Microcrystalline cellulose 13.0 130 Crospovidone 20.0 200  Sodium bicarbonate 3.0 30 Magnesium stearate 1.010 Total 100 1000  *contains 325 mg of acetaminophen

Example 85: Coated Oxycodone Hydrochloride Granules

Oxycodone hydrochloride granules are prepared and subsequently coated.These coated particles are then blended with other components andcompressed into tablets.

TABLE 125 Granules Formulation Component % w/w Hypromellose K100M 54Glyceryl behenate 23 Ethyl cellulose (10 cP) 13 Oxycodone Hydrochloride10 TOTAL 100

TABLE 126 Coated Granules Formulation Component % w/w Oxycodonehydrochloride granules, 10% 40 Eudragit E-100 40 Magnesium stearate 20TOTAL 100

Granules are manufactured in a high shear granulator, where oxycodonehydrochloride, hypromellose, a portion of ethylcellulose and glycerylbehenate is dry mixed for 3 minutes. Then a hydroalcoholic solution ofethyl cellulose 10 cP is slowly added while maintaining the granulatorimpeller and chopper speed at pre-selected values that provide enoughshear for granule formation and growth. Solution addition is continueduntil the entire amount of ethyl cellulose is added. The granules arethen wet milled using a size reduction mill (Granumill) and subsequentlyloaded into fluid bed for drying. The oxycodone hydrochloride granulesare then coated in a bottom spray fluid bed coater with 25% alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate.

Example 86: Oxycodone/Acetaminophen Tablets

The oxycodone hydrochloride coated granules, 4% are prepared accordingto Example 85 above and mixed with another active agent i.e. Paracetamol(manufactured using acetaminophen and gelatin) and other excipients suchas carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose and blended for approximately 270revolutions. Magnesium stearate is then added to lubricate the blend andblended for additional 45 revolutions prior to compressing intooxycodone/acetaminophen tablets.

TABLE 127 Tablet Formulation Component % w/w mg/tablets Oxycodonehydrochloride coated granules, 4% 18.8 188  Paracetamol 34.2 342*Mannitol 5 50 Carbopol 5.0 50 Microcrystalline cellulose 13.0 130 Crospovidone 20.0 200  Sodium bicarbonate 3.0 30 Magnesium stearate 1.010 Total 100 1000  *contains 325 mg of acetaminophen

Example 87: Coated Oxycodone Granules

Oxycodone granules are prepared, and subsequently coated. These coatedparticles are then blended with other components and compressed intotablets.

TABLE 128 Granules Formulation Component % w/w Hypromellose K100M 54Glyceryl behenate 23 Ethyl cellulose (10 cP) 13 Oxycodone Hydrochloride10 TOTAL 100

TABLE 129 Coated Granules Formulation Component % w/w Oxycodonehydrochloride granules, 10% 30 Eudragit E-100 47 Magnesium stearate 23TOTAL 100

Granules are manufactured in a high shear granulator, where oxycodonehydrochloride, hypromellose, a portion of ethyl cellulose and glycerylbehenate is dry mixed for 3 minutes. Then a hydroalcoholic solution ofethyl cellulose 10 cP is slowly added while maintaining the granulatorimpeller and chopper speed at pre-selected values that provide enoughshear for granule formation and growth. Solution addition is continueduntil the entire amount of ethyl cellulose is added. The granules arethen wet milled using a size reduction mill (Granumill) and subsequentlyloaded into fluid bed for drying. The oxycodone hydrochloride granulesare then coated in a bottom spray fluid bed coater with 25% alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate.

Example 88: Oxycodone/Acetaminophen Tablets

The oxycodone hydrochloride coated granules (3%) are prepared accordingto Example 87 above and mixed with another active agent i.e. Paracetamol(manufactured using acetaminophen and gelatin) and other excipients suchas carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose and blended for approximately 270revolutions. Magnesium stearate is then added to lubricate the blend andblended for additional 45 revolutions prior to compressing intooxycodone/acetaminophen tablets.

TABLE 130 Tablet Formulation Component % w/w mg/tablet Oxycodonehydrochloride coated granules, 3% 16.7 167  Paracetamol 34.2 342*Mannitol 7.1 71 Carbopol 5.0 50 Microcrystalline cellulose 13.0 130 Crospovidone 20.0 200  Sodium bicarbonate 3.0 30 Magnesium stearate 1.010 Total 100 1000  *contains 325 mg of acetaminophen

Example 89: Coated Oxycodone Granules

Oxycodone granules are prepared and subsequently coated. These coatedparticles are then blended with other components and compressed intotablets.

TABLE 131 Granules Formulation Component % w/w Hypromellose K100M 56Glyceryl behenate 25 Ethyl cellulose (10 cP) 14 Oxycodone Hydrochloride5 TOTAL 100

TABLE 132 Coated Granules Formulation Component % w/w Oxycodonehydrochloride granules, 5% 70 Eudragit E-100 20 Magnesium stearate 10TOTAL 100

Granules are manufactured in a high shear granulator, where oxycodonehydrochloride, hypromellose, a portion of ethyl cellulose and glycerylbehenate is dry mixed for 3 minutes. Then a hydroalcoholic solution ofethyl cellulose 10 cP is slowly added while maintaining the granulatorimpeller and chopper speed at pre-selected values that provide enoughshear for granule formation and growth. Solution addition is continueduntil the entire amount of ethyl cellulose is added. The granules arethen wet milled using a size reduction mill (Granumill) and subsequentlyloaded into fluid bed for drying. The oxycodone hydrochloride granulesare then coated in a bottom spray fluid bed coater with 25% alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate.

Example 90: Oxycodone/Acetaminophen Tablets

The oxycodone hydrochloride coated granules, 3.5% are prepared accordingto the Example 89 above and mixed with another active agent i.e.Paracetamol (manufactured using acetaminophen and gelatin) and otherexcipients such as carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose and blended for approximately 270revolutions. Magnesium stearate is then added to lubricate the blend andblended for additional 45 revolutions prior to compressing intooxycodone/acetaminophen tablets.

TABLE 133 Tablet Formulation Component % w/w mg/tab Oxycodonehydrochloride coated granules, 3.5% 21.4 214  Paracetamol 34.2 342*Mannitol 2.4 24 Carbopol 5.0 50 Microcrystalline cellulose 13.0 130 Crospovidone 20.0 200  Sodium bicarbonate 3.0 30 Magnesium stearate 1.010 Total 100 1000  *contains 325 mg of acetaminophen

Example 91: Coated Oxycodone Granules

Oxycodone hydrochloride granules are prepared and subsequently coated.These coated particles are then blended with other components andcompressed into tablets.

TABLE 134 Granules Formulation Component % w/w Hypromellose K100M 54.5Glyceryl behenate 24 Ethyl cellulose (10 cP) 14 Oxycodone Hydrochloride7.5 TOTAL 100

TABLE 135 Coated Granules Formulation Component % w/w Oxycodonehydrochloride granules, 7.5% 70 Eudragit E-100 20 Magnesium stearate 10TOTAL 100

Granules are manufactured in a high shear granulator, where oxycodonehydrochloride, hypromellose, a portion of ethyl cellulose and glycerylbehenate is dry mixed for 3 minutes. Then a hydroalcoholic solution ofethyl cellulose 10 cP is slowly added while maintaining the granulatorimpeller and chopper speed at pre-selected values that provide enoughshear for granule formation and growth. Solution addition is continueduntil the entire amount of ethyl cellulose is added. The granules arethen wet milled using a size reduction mill (Granumill) and subsequentlyloaded into fluid bed for drying. The oxycodone hydrochloride granulesare then coated in a bottom spray fluid bed coater with 25% alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate.

Example 92: Oxycodone/Acetaminophen Tablets

The oxycodone hydrochloride coated granules, 5.25% are preparedaccording to the Example 91 above and mixed with another active agenti.e. Paracetamol (manufactured using acetaminophen and gelatin) andother excipients such as carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose and blended for approximately 270revolutions. Magnesium stearate is then added to lubricate the blend andblended for additional 45 revolutions prior to compressing intooxycodone/acetaminophen tablets.

TABLE 136 Tablet Formulation Component % w/w mg/tablet Oxycodonehydrochloride coated granules, 5.25% 19.05  190.5 Paracetamol 34.2 342*Mannitol 4.75   47.5 Carbopol 5.0 50 Microcrystalline cellulose 13.0130  Crospovidone 20.0 200  Sodium bicarbonate 3.0 30 Magnesium stearate1.0 10 Total 100 1000  *contains 325 mg of acetaminophen

Example 93: Hydrocodone/Acetaminophen Tablets

The hydrocodone bitartrate coated granules were prepared according tothe Example 75 and mixed with another active agent i.e. Paracetamol(manufactured using acetaminophen and gelatin) along with otherexcipients such as carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose (blended for approximately 270 revolutions).Magnesium stearate was then added to lubricate the blend and blended foradditional 45 revolutions prior to compressing intohydrocodone/acetaminophen tablets.

TABLE 137 Tablet Formulation Component % w/w mg/tablet Hydrocodonebitartrate coated granules, 5% 20.0 200 Paracetamol 34.21 342.1*Mannitol 3.73 37.3 Carbopol 5.0 50 Microcrystalline cellulose 13.0 130Crospovidone 20.0 200 Sodium bicarbonate 3.0 30 Magnesium stearate 1.010 Iron Oxide Red 0.06 0.6 Total 100 1000 *contains 325 mg ofacetaminophen

Example 94: In Vitro Analysis of Multiple Tablet Oral AbuseResistance—Crushed and Intact Tablets

The dosage form (crushed or intact) prepared according to Example 93 wasevaluated for in vitro multiple tablet oral abuse resistance byconducting dissolution experiments in 300 mL or 900 mL of 0.1N HCl.Dissolution was performed using USP apparatus II at 50 RPM and 37° C.Twelve tablets (crushed or intact) were added to the vesselsimultaneously or sequentially and aliquots were removed periodicallyand were analyzed for hydrocodone bitartrate and APAP by HPLC. Crushingof the tablets was carried out using a morter and pestle (twelvestrokes). The results were plotted against time and appear in FIG. 14and FIG. 15.

Example 95: Esketamine HCl Tablets

Coated granules prepared per Example 31 are subsequently mixed withcoated polymer granules prepared according to Example 71, and othercomponents (carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose) and blended for 270 revolutions. Magnesiumstearate is added to lubricate the blend and the resulting mixture wasblended for additional 45 revolutions prior to compressing into tablets.

TABLE 138 Tablet Formulation Components mg/tablet mg/tablet mg/tabletmg/tablet Esketamine hydro- 87.1 87.1 348.4 348.4 chloride coatedgranules, 28.7% Coated polymer granules 50 31 50 31 Mannitol 37 37 37 37Carbopol 50 50 50 50 Microcrystalline 130 130 130 130 celluloseCrospovidone 200 200 200 200 Sodium bicarbonate 30 30 30 30 Magnesiumstearate 6 6 9 8.5 Total 590.1 571.1 854.4 834.9

Example 96: Esketamine HCl Tablets

Coated granules prepared per Example 31 are subsequently mixed withpolymer granules prepared according to Example 74, and other components(carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended for 270 revolutions. Magnesium stearate is addedto lubricate the blend and the resulting mixture was blended foradditional 45 revolutions prior to compressing into tablets.

TABLE 139 Tablet Formulation Components mg/tablet mg/tablet mg/tabletmg/tablet Esketamine 87.1 87.1 348.4 348.4 hydrochloride coatedgranules, 28.7% Polymer granules 50 27 50 27 Mannitol 37 37 37 37Carbopol 50 50 50 50 Microcrystalline 130 130 130 130 celluloseCrospovidone 200 200 200 200 Sodium bicarbonate 30 30 30 30 Magnesiumstearate 6 6 9 8.5 Total 590.1 567.1 854.4 830.9

Example 97: Esketamine HCl Tablets

The coated granules prepared per Example 27 are subsequently mixed withcoated polymer granules prepared according to Example 71 and othercomponents (carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose) and blended for 270 revolutions. Magnesiumstearate is added to lubricate the blend and the resulting mixture wasblended for additional 45 revolutions prior to compressing into tablets.

TABLE 140 Esketamine hydrochloride tablet compositions Components mg/tab1 mg 2 mg Esketamine hydrochloride coated granules, 2.5% 40 80 Coatedpolymer granules 160 120 mannitol 70 70 carbopol 50 50 microcrystallinecellulose 94 95 Crospovidone 200 200 sodium bicarbonate 30 30 magnesiumstearate 11 18 Total Tablet Weight 655 663

Example 98: Esketamine HCl Tablets

The coated granules prepared per Example 27 above are subsequently mixedwith polymer granules prepared according to Example 74 and othercomponents (carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose) and blended for 270 revolutions. Magnesiumstearate is added to lubricate the blend and the resulting mixture wasblended for additional 45 revolutions prior to compressing into tablets.

TABLE 141 Esketamine hydrochloride tablet compositions Components mg/tab1 mg 2 mg Esketamine hydrochloride coated granules, 2.5% 40 80 polymergranules 80 60 mannitol 70 70 carbopol 50 50 microcrystalline cellulose94 95 Crospovidone 150 150 sodium bicarbonate 30 30 magnesium stearate11 18 Total Tablet Weight 525 553

Example 99: Preparation of Oxycodone HCl Coated Granules forOxycodone/Acetaminophen Tablets

A. Preparation of Polymer Granules

The polymer granules used in the manufacturing of coated oxycodone HClintermediate, 5.0% were manufactured using a high shear wet granulationprocess. The polymer granules batch formula is provided in Table 142,below. The polymer granules manufactured were used in subsequentlayering and coated intermediate batch manufacturing.

TABLE 142 Components for Polymer Granule Formulation Component % w/wHypromellose 60.09 Glyceryl behenate 25.75 Ethyl cellulose 14.16Alcohol* N.A. Purified Water* N.A. TOTAL 100.00  *Alcohol and water wereremoved from the polymer granules during processing.

Granules were manufactured in a high shear granulator, wherehypromellose, glyceryl behenate, and a portion of ethylcellulose weredry mixed. Then, a hydroalcoholic solution of ethylcellulose (10% wt/wt)was slowly added while maintaining the granulator impeller and chopperspeed at pre-selected values that provide enough shear for granuleformation and growth. Solution addition was continued until the entireamount of ethylcellulose was added and granules formed. The granuleswere then wet milled using a size reduction mill (Granumill) and weresubsequently loaded into fluid bed for drying.

B. Manufacturing of Oxycodone Hydrochloride Layered Granules, 10%.

The polymer granules prepared in Part A above were layered with anaqueous solution of HPMC 2910 and oxycodone hydrochloride. The polymergranules were layered in a bottom spray fluid bed coater with a 12%aqueous solution of oxycodone HCl and HPMC 2910.

Using polymer granules prepared in Part A above, the oxycodone HCllayered granules, 10% were manufactured per composition shown in Table143, below.

TABLE 143 Components for Oxycodone Hydrochloride Layered Granule, 10%Formulation Component % w/w Oxycodone Hydrochloride 10.00 Polymergranules (Example 99, Part A, Table 142) 85.00 Hypromellose 2910 5.00Purified Water* NA TOTAL 100.00 *Water was removed from the layeredgranules during processing.

C. Manufacturing of Coated Oxycodone Hydrochloride Intermediate, 5%.

The oxycodone HCl layered granules, 10%, prepared in Part B above, werecoated in a bottom spray fluid bed coater with 25% alcoholic suspensionof Eudragit E-100 copolymer and magnesium stearate. The resulting coatedgranules were blended for homogeneity and subsequently used for furtherblending and compression process.

The oxycodone HCl layered granules, 10% was used in the coating processwhich resulted in a coated oxycodone HCl granule intermediate, 5%, asshown in Table 144 below.

TABLE 144 Components for Coated Oxycodone HCl Intermediate, 5%Formulation Component % w/w Oxycodone Hydrochloride Layered Granules,10% 50.00 Eudragit E-100 33.35 Magnesium stearate 16.65 Alcohol* NATOTAL 100.00  *Alcohol was removed from the intermediate duringprocessing

Example 100: Manufacturing of Oxycodone HCl and Acetaminophen Tablets

Oxycodone HCl and acetaminophen tablets were manufactured by blendingthe coated oxycodone HCl intermediate, 5% (Example 99, manufacturedparts A, B and C above) with acetaminophen and other excipients prior tocompressing into tablets. The composition for Oxycodone HCl andacetaminophen tablets is shown in Table 145.

TABLE 145 Oxycodone HCl and Acetaminophen Tablets 10/325 mg TabletsComponent % w/w mg/tablet Coated Oxycodone HCl Intermediate, 5% 20.00200.0 Paracetamol* 34.21 342.1 Crospovidone 20.00 200.0 MicrocrystallineCellulose 9.00 90.0 Carbopol 71G 2.00 20.0 Sodium Bicarbonate 10.00100.0 Mannitol 3.59 35.9 Magnesium Stearate 1.00 10.0 Colloidal silicondioxide 0.20 2.0 Total 100.00 1000.0 *Equivalent to 32.5% w/w ofacetaminophen per tablet based on composition of 95.0% acetaminophen and5% binder.

Example 101: Manufacturing of Oxycodone HCl and Acetaminophen Tablets

Oxycodone HCl and acetaminophen tablets are manufactured by blending thecoated oxycodone HCl intermediate, 5% (Example 99, manufactured parts A,B and C above) with acetaminophen, coated polymer granules intermediate(prepared according to Example 71) and other excipients prior tocompressing into tablets. The composition for Oxycodone HCl andacetaminophen tablets is shown in Table 146.

TABLE 146 Oxycodone HCl and Acetaminophen Tablets 5/325 mg TabletsComponent % w/w mg/tablet Coated Oxycodone HCl Intermediate, 5% 10.00100.0 Coated Polymer Granules Intermediate 10.00 100.0 Paracetamol*34.21 342.1 Crospovidone 20.00 200.0 Microcrystalline Cellulose 9.0090.0 Carbopol 71G 2.00 20.0 Sodium Bicarbonate 10.00 100.0 Mannitol 3.5935.9 Magnesium Stearate 1.00 10.0 Colloidal silicon dioxide 0.20 2.0Total 100.00 1000.0 *Equivalent to 32.5% w/w of acetaminophen per tabletbased on composition of 95.0% acetaminophen and 5% binder

Example 102: Manufacturing of Oxycodone HCl and Acetaminophen Tablets

Oxycodone HCl and acetaminophen tablets are manufactured by blending thecoated oxycodone HCl intermediate, 5% (Example 99, manufactured parts A,B and C above) with acetaminophen, coated polymer granules intermediate(prepared according to Example 71) and other excipients prior tocompressing into tablets. The composition for Oxycodone HCl andacetaminophen tablets is shown in Table 147.

TABLE 147 Oxycodone HCl and Acetaminophen Tablets 7.5/325 mg TabletsComponent % w/w mg/tablet Coated Oxycodone HCl Intermediate, 5% 15.00150.0 Coated Polymer Granules Intermediate 5.00 50.0 Paracetamol* 34.21342.1 Crospovidone 20.00 200.0 Microcrystalline Cellulose 9.00 90.0Carbopol 71G 2.00 20.0 Sodium Bicarbonate 10.00 100.0 Mannitol 3.59 35.9Magnesium Stearate 1.00 10.0 Colloidal silicon dioxide 0.20 2.0 Total100 1000.0 *Equivalent to 32.5% w/w of acetaminophen per tablet based oncomposition of 95.0% acetaminophen and 5% binder.

Example 103: Manufacturing of Oxycodone HCl and Acetaminophen Tablets

Oxycodone HCl and acetaminophen tablets were manufactured by blendingthe coated oxycodone HCl intermediate, 5% (Example 99, manufacturedparts A, B and C above) with acetaminophen and other excipients prior tocompressing into tablets. The composition for Oxycodone HCl andacetaminophen tablets is shown in Table 148 below.

TABLE 148 Oxycodone HCl and Acetaminophen Tablets 10/325 mg TabletsComponent % w/w mg/tablet Coated Oxycodone HCl Intermediate, 5% 20.00200.0 Paracetamol* 34.21 342.1 Crospovidone 18.50 185.0 MicrocrystallineCellulose 9.00 90.0 Carbopol 71G 0.50 5.0 Sodium Bicarbonate 13.00 130.0Mannitol 3.59 35.9 Magnesium Stearate 1.00 10.0 Colloidal silicondioxide 0.20 2.0 Total 100.00 1000.0 *Equivalent to 32.5% w/w ofacetaminophen per tablet based on composition of 95.0% acetaminophen and5% binder

Example 104: Manufacturing of Oxycodone HCl and Acetaminophen Tablets

Oxycodone HCl and acetaminophen tablets are manufactured by blending thecoated oxycodone HCl intermediate, 5% (Example 99, manufactured parts A,B and C above) with coated polymer granules intermediate (preparedaccording to Example 71), acetaminophen and other excipients prior tocompressing into tablets. The composition for Oxycodone HCl andacetaminophen tablets is shown in Table 149 below.

TABLE 149 Oxycodone HCl and Acetaminophen Tablets 5/325 mg TabletsComponent % w/w mg/tablet Coated Oxycodone HCl Intermediate, 5% 10.00100.0 Coated Polymer Granules Intermediate 10.00 100.0 Paracetamol*34.21 342.1 Crospovidone 18.50 185.0 Microcrystalline Cellulose 9.0090.0 Carbopol 71G 0.50 5.0 Sodium Bicarbonate 13.00 130.0 Mannitol 3.5935.9 Magnesium Stearate 1.00 10.0 Colloidal silicon dioxide 0.20 2.0Total 100.00 1000.0 *Equivalent to 32.5% w/w of acetaminophen per tabletbased on composition of 95.0% acetaminophen and 5% binder.

Example 105: Manufacturing of Oxycodone HCl and Acetaminophen Tablets

Oxycodone HCl and acetaminophen tablets are manufactured by blending thecoated oxycodone HCl intermediate, 5% (Example 99, manufactured parts A,B and C above) with coated polymer granules intermediate (preparedaccording to Example 71), acetaminophen and other excipients prior tocompressing into tablets. The composition for Oxycodone HCl andacetaminophen tablets is shown in Table 150 below.

TABLE 150 Oxycodone HCl and Acetaminophen Tablets 7.5/325 mg TabletsComponent % w/w mg/tablet Coated Oxycodone HCl Intermediate, 5% 15.00150.0 Coated Polymer Granules Intermediate 5.00 50.0 Paracetamol* 34.21342.1 Crospovidone 18.50 185.0 Microcrystalline Cellulose 9.00 90.0Carbopol 71G 0.50 5.0 Sodium Bicarbonate 13.00 130.0 Mannitol 3.59 35.9Magnesium Stearate 1.00 10.0 Colloidal silicon dioxide 0.20 2.0 Total100 1000.0 *Equivalent to 32.5% w/w of acetaminophen per tablet based oncomposition of 95.0% acetaminophen and 5% binder.

Example 106: Preparation of Hydrocodone Bitartrate Coated Granules forHydrocodone/Acetaminophen Tablets

A. Preparation of Polymer Granules

The polymer granules used in the manufacturing of coated hydrocodonebitartrate intermediate, 5.0% were manufactured using a high shear wetgranulation process. The polymer granules batch formula is provided inTable 151, below. The polymer granules manufactured were used insubsequent layering and coated intermediate batch manufacturing.

TABLE 151 Components for Polymer Granule Formulation Component % w/wHypromellose 60.09 Glyceryl behenate 25.75 Ethyl cellulose 14.16Alcohol* N.A. Purified Water* N.A. TOTAL 100.00 *Alcohol and water wereremoved from the polymer granules during processing.

Granules were manufactured in a high shear granulator, wherehypromellose, glyceryl behenate, and a portion of ethylcellulose weredry mixed. Then, a hydroalcoholic solution of ethylcellulose (10% wt/wt)was slowly added while maintaining the granulator impeller and chopperspeed at pre-selected values that provide enough shear for granuleformation and growth. Solution addition was continued until the entireamount of ethylcellulose was added and granules formed. The granuleswere then wet milled using a size reduction mill (Granumill) and weresubsequently loaded into fluid bed for drying.

B. Manufacturing of Hydrocodone Bitartrate Layered Granules, 10%.

The polymer granules prepared in Part A above were layered with anaqueous solution of HPMC 2910 and hydrocodone bitartrate. The polymergranules were layered in a bottom spray fluid bed coater with a 12%aqueous solution of hydrocodone bitartrate and HPMC 2910.

Using polymer granules prepared in Part A above, the hydrocodonebitartrate layered granules, 10% were manufactured per composition shownin Table 152 below.

TABLE 152 Components for Hydrocodone Bitartrate Layered Granule, 10%Formulation Component % w/w Hydrocodone Bitartrate 10.00 Polymergranules (Example 106, Part A, Table 151) 85.00 Hypromellose 2910 5.00Purified Water* NA TOTAL 100.00 *Water was removed from the layeredgranules during processing.

C. Manufacturing of Coated Hydrocodone Bitartrate Intermediate, 5%.

The hydrocodone bitartrate layered granules, 10%, prepared in Part Babove, were coated in a bottom spray fluid bed coater with 25% alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate. Theresulting coated granules were blended for homogeneity and subsequentlyused for further blending and compression process.

The hydrocodone bitartrate layered granules, 10% was used in the coatingprocess which resulted in a coated hydrocodone bitartrate coatedintermediate, 5%, as shown in Table 153, below.

TABLE 153 Components for Coated Hydrocodone Bitartrate Intermediate, 5%Formulation Component % w/w Hydrocodone Bitartrate Layered Granules, 10%50.00 Eudragit E-100 33.35 Magnesium stearate 16.65 Alcohol* NA TOTAL100.00 *Alcohol was removed from the intermediate during processing

Example 107: Manufacturing of Hydrocodone Bitartrate and AcetaminophenTablets

Hydrocodone bitartrate and acetaminophen tablets were manufactured byblending the coated hydrocodone bitartrate intermediate, 5% (Example106, manufactured parts A, B and C above) with acetaminophen and otherexcipients prior to compressing into tablets. The composition forhydrocodone bitartrate and acetaminophen tablets is shown in Table 154.

TABLE 154 Hydrocodone Bitartrate and Acetaminophen Tablets 10/325 mgTablets Component % w/w mg/tablet Coated Hydrocodone BitartrateIntermediate, 5% 20.00 200.0 Paracetamol* 34.21 342.1 Crospovidone 20.00200.0 Microcrystalline Cellulose 9.00 90.0 Carbopol 71G 2.00 20.0 SodiumBicarbonate 10.00 100.0 Mannitol 3.59 35.9 Magnesium Stearate 1.00 10.0Colloidal silicon dioxide 0.20 2.0 Total 100.00 1000.0 *Equivalent to32.5% w/w of acetaminophen per tablet based on composition of 95.0%acetaminophen and 5% binder.

Example 108: Manufacturing of Hydrocodone Bitartrate and AcetaminophenTablets

Hydrocodone bitartrate and acetaminophen tablets are manufactured byblending the coated hydrocodone bitartrate intermediate, 5% (Example106, manufactured parts A, B and C above) with acetaminophen, coatedpolymer granules intermediate (prepared according to Example 71) andother excipients prior to compressing into tablets. The composition forhydrocodone bitartrate and acetaminophen tablets is shown in Table 155.

TABLE 155 Hydrocodone Bitartrate and Acetaminophen Tablets 5/325 mgTablets Component % w/w mg/tablet Coated Hydrocodone BitartrateIntermediate, 5% 10.00 100.0 Coated Polymer Granules Intermediate 10.00100.0 Paracetamol* 34.21 342.1 Crospovidone 20.00 200.0 MicrocrystallineCellulose 9.00 90.0 Carbopol 71G 2.00 20.0 Sodium Bicarbonate 10.00100.0 Mannitol 3.59 35.9 Magnesium Stearate 1.00 10.0 Colloidal silicondioxide 0.20 2.0 Total 100.00 1000.0 *Equivalent to 32.5% w/w ofacetaminophen per tablet based on composition of 95.0% acetaminophen and5% binder.

Example 109: Manufacturing of Hydrocodone Bitartrate and AcetaminophenTablets

Hydrocodone bitartrate and acetaminophen tablets are manufactured byblending the coated hydrocodone bitartrate intermediate, 5% (Example106, manufactured parts A, B and C above) with acetaminophen, coatedpolymer granules intermediate (prepared according to Example 71) andother excipients prior to compressing into tablets. The composition forhydrocodone bitartrate and acetaminophen tablets is shown in Table 156below.

TABLE 156 Hydrocodone bitartrate and Acetaminophen Tablets 7.5/325 mgTablets Component % w/w mg/tablet Coated Hydrocodone BitartrateIntermediate, 5% 15.00 150.0 Coated Polymer Granules Intermediate 5.0050.0 Paracetamol* 34.21 342.1 Crospovidone 20.00 200.0 MicrocrystallineCellulose 9.00 90.0 Carbopol 71G 2.00 20.0 Sodium Bicarbonate 10.00100.0 Mannitol 3.59 35.9 Magnesium Stearate 1.00 10.0 Colloidal silicondioxide 0.20 2.0 Total 100.00 1000.0 *Equivalent to 32.5% w/w ofacetaminophen per tablet based on composition of 95.0% acetaminophen and5% binder.

Example 110: Manufacturing of Hydrocodone Bitartrate and AcetaminophenTablets

Hydrocodone bitartrate and acetaminophen tablets were manufactured byblending the coated hydrocodone bitartrate intermediate, 5% (Example106, manufactured parts A, B and C above) with acetaminophen and otherexcipients prior to compressing into tablets. The composition forhydrocodone bitartrate and acetaminophen tablets is shown in Table 157,below.

TABLE 157 Hydrocodone Bitartrate and Acetaminophen Tablets 10/325 mgTablets Component % w/w mg/tablet Coated Hydrocodone BitartrateIntermediate, 5% 20.00 200.0 Paracetamol* 34.21 342.1 Crospovidone 18.50185.0 Microcrystalline Cellulose 9.00 90.0 Carbopol 71G 0.50 5.0 SodiumBicarbonate 13.00 130.0 Mannitol 3.59 35.9 Magnesium Stearate 1.00 10.0Colloidal silicon dioxide 0.20 2.0 Total 100.00 1000.0 *Equivalent to32.5% w/w of acetaminophen per tablet based on composition of 95.0%acetaminophen and 5% binder.

Example 111: Manufacturing of Hydrocodone Bitartrate and AcetaminophenTablets

Hydrocodone bitartrate and acetaminophen tablets are manufactured byblending the coated hydrocodone bitartrate intermediate, 5% (Example106, manufactured parts A, B and C above) with coated polymer granulesintermediate (prepared according to Example 71), acetaminophen and otherexcipients prior to compressing into tablets. The composition forhydrocodone bitartrate and acetaminophen tablets is shown in Table 158below.

TABLE 158 Hydrocodone Bitartrate and Acetaminophen Tablets 5/325 mgTablets Component % w/w mg/tablet Coated Hydrocodone BitartrateIntermediate, 5% 10.00 100.0 Coated Polymer Granules Intermediate 10.00100.0 Paracetamol* 34.21 342.1 Crospovidone 18.50 185.0 MicrocrystallineCellulose 9.00 90.0 Carbopol 71G 0.50 5.0 Sodium Bicarbonate 13.00 130.0Mannitol 3.59 35.9 Magnesium Stearate 1.00 10.0 Colloidal silicondioxide 0.20 2.0 Total 100.00 1000.0 *Equivalent to 32.5% w/w ofacetaminophen per tablet based on composition of 95.0% acetaminophen and5% binder.

Example 112: Manufacturing of Hydrocodone Bitartrate and AcetaminophenTablets

Hydrocodone bitartrate and acetaminophen tablets are manufactured byblending the coated hydrocodone bitartrate intermediate, 5% (Example106, manufactured parts A, B and C above) with coated polymer granulesintermediate (prepared according to Example 71), acetaminophen and otherexcipients prior to compressing into tablets. The composition forhydrocodone bitartrate and acetaminophen tablets is shown in Table 159below.

TABLE 159 Hydrocodone Bitartrate and Acetaminophen Tablets 7.5/325 mgTablets Component % w/w mg/tablet Coated Hydrocodone BitartrateIntermediate, 5% 15.00 150.0 Coated Polymer Granules Intermediate 5.0050.0 Paracetamol* 34.21 342.1 Crospovidone 18.50 185.0 MicrocrystallineCellulose 9.00 90.0 Carbopol 71G 0.50 5.0 Sodium Bicarbonate 13.00 130.0Mannitol 3.59 35.9 Magnesium Stearate 1.00 10.0 Colloidal silicondioxide 0.20 2.0 Total 100.00 1000.0 *Equivalent to 32.5% w/w ofacetaminophen per tablet based on composition of 95.0% acetaminophen and5% binder.

Example 113: Preparation of Esketamine Coated Granules for EsketamineHCl Tablets

A. Preparation of Polymer Granules

The polymer granules used in the manufacturing of Coated Esketamine HCl,Intermediate, 37% were manufactured using a high shear wet granulationprocess. The polymer granules batch formula is provided in Table 160,below. The polymer granules manufactured were used in a subsequentlayering and coated intermediate batch manufacturing.

TABLE 160 Components for Polymer Granule formulation Component % w/wHypromellose 60.09 Glyceryl behenate 25.75 Ethyl cellulose 14.16Alcohol* N.A. Purified Water* N.A. TOTAL 100.00 *Alcohol and water wereremoved from the polymer granules during processing.

Granules were manufactured in a high shear granulator, wherehypromellose, glyceryl behenate, and a portion of ethylcellulose weredry mixed. Then, a hydroalcoholic solution of ethylcellulose (10% wt/wt)was slowly added while maintaining the granulator impeller and chopperspeed at pre-selected values that provide enough shear for granuleformation and growth. Solution addition was continued until the entireamount of ethylcellulose was added and granules formed. The granuleswere then wet milled using a size reduction mill (Granumill) and weresubsequently loaded into fluid bed for drying.

B. Manufacturing of Esketamine Hydrochloride Layered Granules, 45%.

The polymer granules prepared in Part A above were layered with anaqueous solution of HPMC 2910 and esketamine hydrochloride. The polymergranules were layered in a bottom spray fluid bed coater with a 18%aqueous solution of esketamine HCl and HPMC 2910.

Using polymer granules prepared in Part A above, the esketamine HCllayered granules, 45% were manufactured per composition shown in Table161 below.

TABLE 161 Components for Esketamine HCl Layered Granule, 45% formulationComponent % w/w Esketamine Hydrochloride 45.07 Polymer granules (Example113, Part A, Table 160) 37.60 Hypromellose 2910 17.33 Purified Water* NATOTAL 100.00 *Water was removed from the layered granules duringprocessing.

C. Manufacturing of Coated Esketamine Hydrochloride Intermediate, 37%.

The Esketamine HCl layered granules, 45%, prepared in Part B above, werecoated in a bottom spray fluid bed coater with 25% alcoholic suspensionof Eudragit E-100 copolymer and magnesium stearate.

The esketamine HCl layered granules, 45% was used in the coating processwhich resulted in a coated esketamine HCl coated intermediate, 37%, asshown in Table 162 below.

TABLE 162 Components for Esketamine HCl Coated Intermediate, 37%formulation Component % w/w Esketamine Hydrochloride Layered Granules,45% 81.99 Eudragit E-100 12.00 Magnesium stearate 6.00 Alcohol* NA TOTAL100.0 *Alcohol was removed from the intermediate during processing

Example 114A, 114B and 114C: Manufacturing of Esketamine HCl Tablets

Esketamine HCl tablets were manufactured by blending the coatedesketamine HCl intermediate, 37% (Example 113, manufactured parts A, Band C above) with coated polymer granules (prepared according to Example71) and other excipients prior to compressing into tablets. Thecomposition for Esketamine HCl tablets is shown in Table 163.

TABLE 163 Esketamine HCl Tablets 100 mg Tablets Example 114A Example114B Example 114C Component % w/w mg/tab % w/w mg/tab % w/w mg/tabCoated Esketamine 27.03 270.30 27.03 270.30 27.03 270.30 HClIntermediate, 37% Coated Polymer Granule 20.00 200.00 20.00 200.00 20.00200.00 Mannitol 10.97 109.70 6.97 69.70 6.97 69.70 Crospovidone 20.00200.00 20.00 200.00 18.50 185.00 Microcrystalline Cellulose 13.00 130.0013.00 130.00 13.00 130.00 Sodium Bicarbonate 3.00 30.00 10.00 100.0013.00 130.00 Carbopol 71G 5.00 50.00 2.00 20.00 0.50 5.00 MagnesiumStearate 1.00 10.00 1.00 10.00 1.00 10.00 Total 100.00 1000.00 100.001000.00 100.00 1000.00

What is claimed is:
 1. An immediate release abuse deterrent dosage formcomprising: core-shell particles comprising a core comprising a gellingpolymer, wherein the core does not include microcrystalline cellulose, asugar sphere, or an active pharmaceutical agent; an activepharmaceutical layer surrounding the core, the active pharmaceuticallayer comprising a narcotic analgesic; and at least one layersurrounding the active pharmaceutical layer, the at least one layercomprising a pH-sensitive film comprising a pH-sensitive polymer that isinsoluble in water at a pH greater than 5 and is soluble in water at apH below 5; wherein the dosage form demonstrates an immediate releaseprofile of the narcotic analgesic when administered to a human intherapeutic doses and an extended release profile of the narcoticanalgesic when administered to a human in supratherapeutic doses.
 2. Thedosage form according to claim 1, wherein the supratherapeutic dose isfive or more tablets.
 3. The dosage form according to claim 1, whereinthe dosage form is in a compressed tablet form.
 4. The dosage formaccording to claim 1, wherein at least 90 percent of the total amount ofthe narcotic analgesic in the core shell particles is contained in theactive pharmaceutical layer.
 5. The dosage form according to claim 1,further comprising a second type of core-shell particles that do notcontain an active pharmaceutical layer, the second type of core-shellparticles comprising: a core, the core comprising a gelling polymer,wherein the gelling polymer in the core is selected from a naturalstarch, a synthetic starch, a natural cellulose, a synthetic cellulose,an acrylate, a polyalkylene oxide, a carbomer and combinations thereof;and at least one layer surrounding the core, the at least one layercomprising a pH-sensitive film comprising pH-sensitive polymer that isinsoluble at a pH greater than 5 and is soluble at a pH below
 5. 6. Thedosage form according to claim 1, wherein the narcotic analgesic is anopioid.
 7. The dosage form according to claim 6, wherein the dosage formfurther comprises a nonsteroidal analgesic drug.
 8. The dosage formaccording to claim 6, wherein the opioid is selected from buprenorphine,codeine, dihydrocodeine, dihydromorphine, hydrocodone, hydromorphone,morphine, oxycodone, oxymorphone, and pharmaceutically acceptable saltsthereof.
 9. The dosage form according to claim 7, wherein thenonsteroidal analgesic drug is selected from acetaminophen, aspirin,ibuprofen and naproxen.
 10. The dosage form according to claim 1,wherein the gelling polymer in the core is selected from ethylcellulose,cellulose acetate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate, celluloseether, cellulose ester, cellulose ester ether, cellulose, hydroxypropylmethyl cellulose, hydroxy methyl cellulose, methyl cellulose,hydroxyethylmethyl cellulose, sodium carboxymethyl cellulose, a carbomerpolymer, polyethylene oxide, and combinations thereof.
 11. The dosageform according to claim 1, further comprising a matrix.
 12. The dosageform according to claim 11, wherein the matrix comprises a gellingpolymer.
 13. The dosage form according to claim 12, wherein the gellingpolymer in the matrix is selected from a synthetic cellulose, apolyalkylene oxide, a carbomer, and combinations thereof.
 14. The dosageform according to claim 12, wherein the gelling polymer in the matrix isa carbomer.
 15. The dosage form according to claim 12, wherein, whereinthe gelling polymer in the matrix is present in an amount from 0.5 to 15weight percent based on the total weight of the dosage form.
 16. Thedosage form according to claim 1, wherein the pH-sensitive polymer is acopolymer of dimethyl aminoethyl methacrylate, butyl methacrylate, andmethyl methacrylate monomers.
 17. The dosage form according to claim 1,wherein the dosage form excludes an emetic, a nasal irritant, an opioidantagonist, and an effervescent.
 18. The dosage form according to claim1, wherein the dosage form reduces the risk of an overdose of thenarcotic analgesic by simultaneous oral ingestion of multiple units ofthe oral dosage form.
 19. A method of reducing the potential for abuseby a human of a narcotic analgesic drug by simultaneous oral ingestionof multiple dosage units of said narcotic analgesic drug, the methodcomprising providing an immediate release abuse deterrent dosage formaccording to claim
 1. 20. The method according to claim 19, wherein atleast 90 percent of the total amount of the narcotic analgesic in thecore shell particles is contained in the active pharmaceutical layer.21. The method according to claim 19, wherein the dosage form furthercomprises a second type of core-shell particles that do not contain anactive pharmaceutical layer, the second type of core-shell particlescomprising: a core, the core comprising a gelling polymer, wherein thegelling polymer in the core is selected from a natural starch, asynthetic starch, a natural cellulose, a synthetic cellulose, anacrylate, a polyalkylene oxide, a carbomer and combinations thereof; andat least one layer surrounding the core, the at least one layercomprising a pH-sensitive film comprising pH-sensitive polymer that isinsoluble at a pH greater than 5 and is soluble at a pH below
 5. 22. Themethod according to claim 19, wherein the narcotic analgesic is anopioid.
 23. The method according to claim 22, wherein the dosage formfurther comprises a nonsteroidal analgesic drug.
 24. The methodaccording to claim 22, wherein the opioid is selected frombuprenorphine, codeine, dihydrocodeine, dihydromorphine, hydrocodone,hydromorphone, morphine, oxycodone, oxymorphone, and pharmaceuticallyacceptable salts thereof.
 25. The method according to claim 23, whereinthe nonsteroidal analgesic drug is selected from acetaminophen, aspirin,ibuprofen and naproxen.
 26. The method according to claim 19, whereinthe gelling polymer in the core is selected from ethylcellulose,cellulose acetate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate, celluloseether, cellulose ester, cellulose ester ether, cellulose, hydroxypropylmethyl cellulose, hydroxy methyl cellulose, methyl cellulose,hydroxyethylmethyl cellulose, sodium carboxymethyl cellulose, a carbomerpolymer, polyethylene oxide, and combinations thereof.
 27. The methodaccording to claim 19, wherein the dosage form further comprises amatrix comprising a gelling polymer, and wherein the gelling polymer inthe matrix is a carbomer polymer.
 28. The method according to claim 27,wherein, wherein the gelling polymer in the matrix is present in anamount from 0.5 to 15 weight percent based on the total weight of thedosage form.
 29. The method according to claim 19, wherein thepH-sensitive polymer is a copolymer of dimethyl aminoethyl methacrylate,butyl methacrylate, and methyl methacrylate monomers.
 30. The methodaccording to claim 19, wherein the dosage form excludes an emetic, anasal irritant, an opioid antagonist, and an effervescent.
 31. Themethod according to claim 19, wherein the dosage form reduces the riskof an overdose of the narcotic analgesic by simultaneous oral ingestionof multiple units of the oral dosage form.
 32. The method according toclaim 19, wherein the dosage form that demonstrates an immediate releaseprofile when administered in therapeutic doses, but which demonstratesan extended release profile when administered in supratherapeutic doses.33. The method according to claim 32, wherein the supratherapeutic doseis five or more tablets.